Dihydropteridinones ii

ABSTRACT

The present invention relates to spiroheterocycl-dihydropyrimidines, their use as modulators of γ-secretase and to pharmaceutical compositions containing said compounds. In particular, the present invention relates to compounds which interfere with γ-secretase and/or its substrate and therefore modulate the formation of Aβ peptides.

FIELD OF THE INVENTION

The present invention relates to dihydropteridinones, their use asmodulators of γ-secretase and to pharmaceutical compositions containingsaid compounds. In particular, the present invention relates tocompounds which interfere with γ-secretase and/or its substrate andtherefore modulate the formation of Aβ peptides. Accordingly thesecompounds can be used for the treatment of Aβ-related pathologies.

In addition, the invention relates to processes for preparingpharmaceutical compositions as well as compounds according to theinvention.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is the most prevalent form of dementia. Thisneurodegenerative disorder is characterized by two major pathologies,β-amyloid deposits and neurofibrillary tangles. Clinically, AD ischaracterized by the loss of memory, cognition, reasoning, judgement aswell as orientation. As the disease progresses, further abilities arelost until a global impairment of multiple cognitive functions occur.These cognitive losses take place gradually, but typically lead tosevere impairment and eventual death in 4-12 years.

β-amyloid deposits are predominantly formed from aggregated Aβ peptide.The Aβ peptide is formed from amyloid precursor protein (APP) throughtwo independent proteolytic events involving β-secretase followed byγ-secretase. Variability in the site of proteolysis via γ-secretaseresults in Aβ species of variable length, the most predominant forms ofwhich are Aβ38, Aβ40 and Aβ42. The secreted Aβ then aggregates intooligomeric species, which further aggregate to ultimately form the Aβdeposits detected in the brains of AD patients. The aggregatedoligomeric species are widely believed to be the key neurotoxic agentresponsible for the neurodegeneration detected in the brains of ADpatients. Of the various Aβ species generated by γ-secretase, Aβ42 hasbeen demonstrated to be the most aggregation prone as well as the mostneurotoxic Aβ species. Furthermore, human genetics strongly supports akey role of Aβ42 as a key mediator of AD pathogenesis. More than 150different mutations causing familial AD are known which result fromeither an increase in the ratio of Aβ42/Aβ40 peptides produced orincrease the intrinsic aggregation propensity of Aβ. Based on thisknowledge, therapeutic approaches aimed at lowering levels of Aβ42 areconsidered promising.

β-amyloid deposits and vascular amyloid angiopathy have also beencharacterized in the brains of patients with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-type (HCHWA-D), and other neurodegenerative disorders.

γ-Secretase inhibitors completely inhibit the cleavage of APP as well asall other substrates of γ-secretase. This inhibition leads to asimultaneous inhibition of the production of all Aβ species. As opposedto γ-secretase inhibitors, γ-secretase modulators preferentially blockthe production of the neurotoxic Aβ42 species while not inhibiting APPcleavage and thereby the generation of all Aβ species. Furthermore,γ-Secretase modulators do not inhibit the cleavage of other γ-secretasesubstrates, thereby diminishing the possibility of side effects. WO2010/053438 discloses compounds of the following core structure

and their use as medicaments in the treatment of diseases likeAlzheimer's disease. WO 2010/132015 discloses compounds of the followingcore structures,

which interfere with gamma-secretase and/or its substrates and modulateβ-amyloid peptide production.

Aim of the Invention

It has now been found that compounds of the present invention accordingto general formula I are effective modulators of γ-secretase.

Accordingly, one aspect of the present invention relates to compoundsaccording to formula I and salts thereof as modulators of γ-secretase.

A further aspect of the invention relates to the physiologicallyacceptable salts of the compounds of general formula I according to thisinvention with inorganic or organic acids.

In a further aspect this invention relates to pharmaceuticalcompositions, containing at least one compound according to formula I ora physiologically acceptable salt thereof, optionally together with oneor more inert carriers and/or diluents.

A further aspect of the present invention relates to compounds accordingto formula I or a physiologically acceptable salt thereof orpharmaceutical compositions comprising compounds according to formula Ior physiologically acceptable salts thereof for the use in theprevention and/or treatment of Aβ-related pathologies. In a furtheraspect this invention relates to pharmaceutical compositions, containingat least one compound according to formula I or a physiologicallyacceptable salt thereof, optionally together with one or more inertcarriers and/or diluents.

A further aspect of the present invention relates to compounds accordingto formula I or a physiologically acceptable salt thereof orpharmaceutical compositions comprising compounds according to formula Ior physiologically acceptable salts thereof for the use in theprevention and/or treatment of diseases or conditions which can beinfluenced by modulating Aβ peptides, such as Aβ-related pathologieslike Down's syndrome, Abeta-amyloid angiopathy, cerebral amyloidangiopathy, hereditary cerebral hemorrhage, a disorder associated withcognitive impairment, MCI (“mild cognitive impairment”), Alzheimer'sDisease, memory loss, attention deficit symptoms associated withAlzheimer's disease, neurodegeneration associated with Alzheimer'sdisease, diffuse Lewy body type of Alzheimer's Disease, dementia ofmixed vascular origin, dementia of degenerative origin, pre-seniledementia, senile dementia, dementia associated with Parkinson's disease,progressive supranuclear palsy or cortical basal degeneration, the dryform of age-related macular degeneration and glaucoma.

Other aims of the present invention will become apparent to the skilledman directly from the foregoing and following remarks.

DETAILED DESCRIPTION

In a first aspect the present invention relates to compounds of generalformula I

wherein

-   A is selected from the group A^(a) consisting of    -   a heteroaryl group with 5 or 6 ring atoms containing one to        three heteroatoms independently selected from N, O, S,        -   wherein above mentioned heteroaryl groups may optionally be            substituted with 1 or 2 substituents independently selected            from the group consisting of halogen, cyano, C₁₋₆-alkyl-,            HO—C₁₋₆-alkyl-, which is optionally fluorinated with 1 to 13            fluorine atoms, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₃-alkyl-,            C₁₋₄-alkyl-O— which is optionally fluorinated with 1 to 9            fluorine atoms and (C₁₋₄-alkyl)₃Si—;-   B is selected from the group B^(a) consisting of

-   -   wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-,        pyridazinyl and pyrazinyl groups may optionally be substituted        with 1 or 2 substituents independently selected from the group        consisting of HO—, halogen, cyano, C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-O— and C₁₋₆-alkyl-O— which is optionally        fluorinated with 1 to 13 fluorine atoms;

-   D is selected from the group D^(a) consisting of    -   a 4- to 12-membered mono-, bicyclic or bridged heterocyclyl        group, or a 3- to 12-membered mono- or bicyclic carbocyclyl        group,        -   wherein above mentioned group D^(a) may optionally be            substituted with 1 to 4 substituents independently selected            from the group consisting of halogen, cyano, C₁₋₆-alkyl-            which is optionally fluorinated with 1 to 13 fluorine atoms,            C₃₋₆-cycloalkyl-, heterocyclyl, aryl, aryl-C₁₋₃-alkyl-,            heteroaryl, heteroaryl-C₁₋₃-alkyl-, HC(O)—,            C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—,            C₁₋₄-alkyl-O—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—, HO—, oxo,            C₁₋₆-alkyl-O— which is optionally fluorinated with 1 to 13            fluorine atoms, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,            aryl-O—, heteroaryl-O—, H₂N—, (C₁₋₄-alkyl)₂N—, azetidinyl,            pyrrolidinyl and (C₁₋₄-alkyl)(C₁₋₃-alkyl-C(O))N—, and            -   wherein above mentioned aryl-C(O)—, aryl-O—, aryl,                aryl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl- and                heteroaryl-O— groups may optionally be substituted with                1 to 3 substituents independently selected from the                group consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₃C—,                F₂HCO—, FH₂CO—, heterocyclyl-O—, cyano, halogen, F₅S—,                (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—,                (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,                (C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and                C₁₋₆-alkyl- which is optionally fluorinated with 1 to 13                fluorine atoms;

-   W is selected from the group W^(a) consisting of    -   —(R⁷)N— and —O—;

-   R¹ is selected from the group R^(1a) consisting of    -   H, C₁₋₈-alkyl-, C₂₋₈-alkenyl-, C₂₋₈-alkynyl-, carbocyclyl,        carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,        heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,        heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—C₁₋₃-alkyl-, R⁴O—, R⁴S(O)_(m)—        with m=0, 1, 2,        -   wherein above mentioned C₁₋₈-alkyl-, C₂₋₈-alkenyl-,            C₂₋₈-alkynyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,            C-linked heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl,            aryl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl- and            R⁴R⁵N—C₁₋₃-alkyl- groups may optionally be substituted with            1 to 3 substituents independently selected from the group            consisting of HO—, oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,            heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—,            nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,                (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groups may                optionally be substituted with 1 to 13 fluorine atoms;

-   R² is selected from the group R^(ea) consisting of    -   H, C₁₋₈-alkyl-, C₂₋₈-alkenyl-, C₂₋₈-alkynyl-, carbocyclyl,        carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,        heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,        heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—, R⁴R⁵N—C₁₋₃-alkyl-, R⁴R⁵N—C(O)—        and R⁴O—,        -   wherein above mentioned C₁₋₈-alkyl-, C₂₋₈-alkenyl-,            C₂₋₈-alkynyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,            C-linked heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl,            aryl-C₁₋₃-alkyl-, heteroaryl and            heteroaryl-C₁₋₃-alkyl-groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen, F₅S—,            (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl- and C₁₋₆-alkyl-,            and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,                (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl- and                C₁₋₆-alkyl- may optionally be substituted with 1 to 13                fluorine atoms;

-   R³ is selected from the group R^(3a) consisting of    -   H, C₁₋₈-alkyl-, C₂₋₈-alkenyl-, C₂₋₈-alkynyl-, carbocyclyl,        carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,        heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,        heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—, R⁴R⁵N—C₁₋₃-alkyl-, and R⁴O—,        -   wherein above mentioned C₁₋₈-alkyl-, C₂₋₈-alkenyl-,            C₂₋₈-alkynyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,            C-linked heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl,            aryl-C₁₋₃-alkyl-, heteroaryl and            heteroaryl-C₁₋₃-alkyl-groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen, F₅S—,            (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,                (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groups may                optionally be substituted with 1 to 13 fluorine atoms;

-   R⁴, R⁵ are selected independently of each other from the group    R^(4a)/R^(5a) consisting of    -   H, C₁₋₆-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,        carbocyclyl-O—C₂₋₄-alkyl-, heterocyclyl,        heterocyclyl-C₁₋₆-alkyl-, heterocyclyl-O—C₂₋₄-alkyl-, aryl,        aryl-C₁₋₃-alkyl-, aryl-O—C₂₋₃-alkyl-, heteroaryl,        heteroaryl-C₁₋₃-alkyl- and heteroaryl-O—C₂₋₃-alkyl-,        -   wherein above mentioned C₁₋₆-alkyl-, carbocyclyl,            carbocyclyl-C₁₋₃-alkyl-, carbocyclyl-O—C₂₋₄-alkyl-,            heterocyclyl, heterocyclyl-C₁₋₆-alkyl- or            heterocyclyl-O—C₂₋₄-alkyl- groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of halogen, cyano, HO—, oxo,            C₁₋₄-alkyl-O— which is optionally fluorinated with 1 to 9            fluorine atoms, C₁₋₄-alkyl-O—C(O)—, HO—C₁₋₄-alkyl-,            C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl, (C₁₋₄-alkyl)₂N—,            (C₁₋₃-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms,        -   wherein above mentioned aryl-, aryl-C₁₋₃-alkyl-,            aryl-O—C₂₋₃-alkyl-, heteroaryl-, heteroaryl-C₁₋₃-alkyl- and            heteroaryl-O—C₂₋₃-alkyl- groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—,            F₂HCO—, FH₂CO—, heterocyclyl-O—, cyano, halogen, F₅S—,            (C₁₋₄-alkyl)₃Si—, nitro, (R⁶)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms, or    -   R^(4a) and R^(5a) form together with the nitrogen atom to which        they are attached a 4-12-membered mono-, bicyclic or bridged        ring system optionally containing one or two double bonds and/or        one aromatic ring and optionally containing one or two        additional heteroatoms selected from the group consisting of        —O—, —S—, —S(O)—, —S(O)₂—, —N(R⁶)—,        -   wherein 2 geminal hydrogen atoms of the 4-12-membered mono-            or bicyclic ring system may be replaced by a —(CH₂)₁₋₅—            group and            -   wherein one —(CH₂)— group of the —(CH₂)₁₋₅— group may be                replaced by —O— or —N(R⁶)— and        -   wherein above mentioned 4-12-membered mono-, bicyclic or            bridged ring system may optionally be substituted with 1 or            2 substituents independently selected from the group            consisting of halogen, cyano, aryl, heteroaryl,            aryl-C₁₋₃-alkyl-, C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms, heterocyclyl, HO—,            oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-O—C(O)—,            HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,            C₃₋₆-cycloalkyl-O—C₁₋₄-alkyl-, heterocyclyl-O—,            heterocyclyl-O—C₁₋₄-alkyl-, aryl-O—, heteroaryl-O— and            (R⁶)₂N—,            -   wherein the directly above mentioned aryl,                aryl-C₁₋₃-alkyl-, aryl-O—, heteroaryl-O—, and heteroaryl                groups may optionally be substituted with 1 to 3                substituents independently selected from the group                consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,                heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—,                nitro, amino, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which is                optionally fluorinated with 1 to 13 fluorine atoms;

-   R⁶ is selected independently of each other from the group R^(ha)    consisting of    -   H, C₁₋₆-alkyl-, C₃₋₆-cycloalkyl, heterocyclyl, heteroaryl,        HC(O)—, C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—,        C₁₋₄-alkyl-O—C(O)— and (C₁₋₄-alkyl)₂N—C(O)—,        -   wherein above mentioned C₁₋₆-alkyl-, C₃₋₆-cycloalkyl-,            C₁₋₆-alkyl-C(O)— and C₃₋₆-cycloalkyl-C(O)— groups may            optionally be substituted with 1-13 fluorine atoms        -   wherein the above mentioned aryl-C(O)— and heteroaryl group            may optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of HO—,            C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—, heterocyclyl-O—,            cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, amino,            (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,            (C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and            C₁₋₆-alkyl- which is optionally fluorinated with 1 to 13            fluorine atoms;

-   R⁷ is selected from the group R^(7a) consisting of    -   H and C₁₋₅-alkyl- which is optionally fluorinated with 1 to 13        fluorine atoms,        the tautomers thereof, the stereoisomers thereof, the mixtures        thereof and the salts thereof.

Unless otherwise stated, the groups, residues, and substituents,particularly R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A, B, D and W are defined asabove and hereinafter. If residues, substituents, or groups occurseveral times in a compound they may have the same or differentmeanings. Some preferred meanings of groups and substituents of thecompounds according to the invention will be given hereinafter.

In a further embodiment of the present invention

-   A is selected from the group A^(b) consisting of

-   -   wherein above mentioned groups may optionally be substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen, cyano, and C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   A is selected from the group A^(c) consisting of

-   -   wherein above mentioned groups may optionally be substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen and C₁₋₃-alkyl- which is optionally        fluorinated with 1 to 7 fluorine atoms.

In a further embodiment of the present invention

-   A is selected from the group A^(d) consisting of

-   -   wherein above mentioned groups may optionally be substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen and C₁₋₃-alkyl- which is optionally        fluorinated with 1 to 7 fluorine atoms.

In a further embodiment of the present invention

-   A is selected from the group A^(e) consisting of

-   -   wherein above mentioned groups may optionally be substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen and C₁₋₃-alkyl- which is optionally        fluorinated with 1 to 7 fluorine atoms.

In a further embodiment of the present invention

-   B is selected from the group B^(b) consisting of

-   -   wherein above mentioned phenyl- and pyridinyl-groups may        optionally be substituted with 1 or 2 substituents independently        selected from the group consisting of HO—, halogen, cyano,        C₁₋₆-alkyl- which is optionally fluorinated with 1 to 13        fluorine atoms, C₃₋₆-cycloalkyl-O— and C₁₋₆-alkyl-O— which is        optionally fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   B is selected from the group B^(c) consisting of

-   -   wherein above mentioned phenyl- and pyridinyl- groups may        optionally be substituted with 1 or 2 substituents independently        selected from the group consisting of halogen, cyano,        C₁₋₃-alkyl- which is optionally fluorinated with 1 to 7 fluorine        atoms, and C₁₋₃-alkyl-O— which is optionally fluorinated with 1        to 7 fluorine atoms.

In a further embodiment of the present invention

-   D is selected from the group D^(b) consisting of

-   -   wherein above mentioned ring system D^(b) may optionally be        substituted with 1 to 4 substituents independently selected from        the group consisting of halogen, cyano, C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-, heterocyclyl, aryl, aryl-C₁₋₃-alkyl-,        heteroaryl, heteroaryl-C₁₋₃-alkyl-, HC(O)—, C₁₋₆-alkyl-C(O)—,        C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—, C₁₋₄-alkyl-O—C(O)—,        (C₁₋₄-alkyl)₂N—C(O)—, HO—, oxo, C₁₋₆-alkyl-O— which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, aryl-O—, heteroaryl-O—,        H₂N—, (C₁₋₄-alkyl)₂N—, azetidinyl, pyrrolidinyl and        (C₁₋₄-alkyl)(C₁₋₃-alkyl-C(O))N—, and        -   wherein above mentioned aryl-C(O)—, aryl-O—, aryl,            aryl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl- and            heteroaryl-O— groups may optionally be substituted with 1 to            3 substituents independently selected from the group            consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₃C—, F₂HCO—,            FH₂CO—, heterocyclyl-O—, cyano, halogen, F₅S—,            (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   D is selected from the group D^(c) consisting of

-   -   wherein above mentioned ring system D^(c) may optionally be        substituted with 1 to 4 substituents independently selected from        the group consisting of halogen, cyano, C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-, heterocyclyl, aryl, aryl-C₁₋₃-alkyl-,        heteroaryl, heteroaryl-C₁₋₃-alkyl-, HC(O)—, C₁₋₆-alkyl-C(O)—,        C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—, C₁₋₄-alkyl-O—C(O)—,        (C₁₋₄-alkyl)₂N—C(O)—, HO—, oxo, C₁₋₆-alkyl-O— which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, aryl-O—, heteroaryl-O—,        H₂N—, (C₁₋₄-alkyl)₂N—, azetidinyl, pyrrolidinyl and        (C₁₋₄-alkyl)(C₁₋₃-alkyl-C(O))N—, and        -   wherein above mentioned aryl-C(O)—, aryl-O—, aryl,            aryl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl- and            heteroaryl-O— groups may optionally be substituted with 1 to            3 substituents independently selected from the group            consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₃C—, F₂HCO—,            FH₂CO—, heterocyclyl-O—, cyano, halogen, F₅S—,            (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   D is selected from the group D^(d) consisting of

-   -   wherein above mentioned ring D^(d) may optionally be substituted        with 1 to 4 substituents independently selected from the group        consisting of halogen, cyano, C₁₋₆-alkyl- which is optionally        fluorinated with 1 to 13 fluorine atoms, C₃₋₆-cycloalkyl-,        oxetanyl, tetrahydrofuryl, tetrahydropyranyl, phenyl,        phenyl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl-, HC(O)—,        C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, phenyl-C(O)—,        C₁₋₄-alkyl-O—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—, HO—, oxo,        C₁₋₆-alkyl-O— which is optionally fluorinated with 1 to 13        fluorine atoms, C₃₋₆-cycloalkyl-O—, oxetanyl-O—,        tetrahydrofuryl-O—, tetrahydropyranyl-O—, phenyl-O—,        heteroaryl-O—, H₂N—, (C₁₋₄-alkyl)₂N—, azetidinyl, pyrrolidinyl        and (C₁₋₄-alkyl)(C₁₋₃-alkyl-C(O))N—, and        -   wherein above mentioned phenyl, phenyl-C₁₋₃-alkyl-,            heteroaryl-C₁₋₃-alkyl-, phenyl-C(O)—, phenyl-O—, heteroaryl-            and heteroaryl-O— group may optionally be substituted with 1            to 3 substituents independently selected from the group            consisting of HO—, C₁₋₄ ^(alkyl-O—, F) ₃C—, F₃C—, F₂HCO—,            FH₂CO—, oxetanyl-O—, tetrahydrofuryl-O—,            tetrahydropyranyl-O—, cyano, halogen, F₅S—,            (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   D is selected from the group D^(e) consisting of

-   -   wherein above mentioned rings D^(e) may optionally be        substituted with 1 to 4 substituents independently selected from        the group consisting of halogen, cyano, C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-, phenyl- wherein above mentioned phenyl may        optionally be substituted with 1 to 3 substituents independently        selected from the group consisting of C₁₋₄-alkyl-O—, F₃C—,        F₂HCO—, FH₂CO—, cyano, halogen, F₅S— and C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   D is selected from the group D^(f) consisting of

-   -   wherein above mentioned rings D^(e) may optionally be        substituted with 1 to 4 substituents independently selected from        the group consisting of halogen, cyano, C₁₋₆-alkyl- which is        optionally fluorinated with 1 to 13 fluorine atoms,        C₃₋₆-cycloalkyl-, phenyl-C₁₋₃-alkyl- and phenyl-, and        -   wherein above mentioned phenyl-C₁₋₃-alkyl- and phenyl-            groups may optionally be substituted with 1 to 3            substituents independently selected from the group            consisting of C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—, cyano,            halogen, F₅S— and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   D is selected from the group D^(g) consisting of

-   -   wherein above mentioned ring Dg may optionally be substituted        with 1 to 2 substituents independently selected from the group        consisting of phenyl, phenyl-C₁₋₃-alkyl-, fluoro, C₁₋₆-alkyl-        and C₁₋₃-alkyl-O—, and        -   wherein above mentioned phenyl and phenyl-C₁₋₃-alkyl- groups            may optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of            C₁₋₄-alkyl-O—, F₃C—, F₃CO—, F₂HCO—, FH₂CO—, cyano, halogen,            and C₁₋₃-alkyl-.

In a further embodiment of the present invention

-   D is selected from the group D^(h) consisting of

In a further embodiment of the present invention

-   W is selected from the group W^(b) consisting of    -   —(R⁷)N—.

In a further embodiment of the present invention

-   R¹ is selected from the group R^(1b) consisting of    -   H, C₁₋₈-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked        heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, heteroaryl,        heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—C₁₋₃-alkyl-, R⁴O—, and R⁴S(O)_(m)—        with m=0, 1, 2        -   wherein above mentioned C₁₋₈-alkyl-, carbocyclyl,            carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,            heterocyclyl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl-            and R⁴R⁵N—C₁₋₃-alkyl- groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen, H₂N—,            (C₁₋₄-alkyl)₂N—, (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,            (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,                (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- may optionally                be substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R¹ is selected from the group R^(1c) consisting of    -   H, C₁₋₈-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked        heterocyclyl, and heterocyclyl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₈-alkyl-, carbocyclyl,            carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl and            heterocyclyl-C₁₋₃-alkyl-groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- may optionally                be substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R¹ is selected from the group R^(id) consisting of    -   H, C₁₋₅-alkyl-, C₃₋₆-cycloalkyl-, C₃₋₆-cycloalkyl-C₁₋₂-alkyl-,        R⁴R⁵N—C₁₋₃-alkyl-, C-linked heterocyclyl and        heterocyclyl-C₁₋₆-alkyl-,    -   wherein the heterocyclyl-groups are selected from the group        consisting of

-   -   -   wherein above mentioned C₁₋₅-alkyl-, C₃₋₆-cycloalkyl-,            C₃₋₆-cycloalkyl-C₁₋₂-alkyl-, C-linked heterocyclyl and            heterocyclyl-C₁₋₃-alkyl-groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groups may                optionally be substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R¹ is selected from the group R^(1e) consisting of    -   H, C₁₋₆-alkyl-, C₃₋₆-cycloalkyl-, C₃₋₆-cycloalkyl-C₁₋₂-alkyl-,        C-linked heterocyclyl, heterocyclyl-C₁₋₆-alkyl-,    -   wherein the C-linked heterocyclyl-groups are selected from the        group consisting of

-   -   -   wherein above mentioned C₁₋₅-alkyl-, C₃₋₆-cycloalkyl-,            C₃₋₆-cycloalkyl-C₁₋₂-alkyl-, C-linked heterocyclyl and            heterocyclyl-C₁₋₃-alkyl-groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen,            C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groups may                optionally be substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R¹ is selected from the group R^(1f) consisting of    -   H, C₁₋₄-alkyl-,        -   wherein above mentioned C₁₋₈-alkyl-groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of HO—, C₁₋₃-alkyl-O—, cyano, and            halogen.

In a further embodiment of the present invention

-   R² is selected from the group R^(2b) consisting of    -   H, C₁₋₈-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked        heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-,        heteroaryl, heteroaryl-C₁₋₃-alkyl- and R⁴R⁵N—C₂₋₃-alkyl-,        -   wherein above mentioned C₁₋₈-alkyl-, carbocyclyl,            carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,            heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl            and heteroaryl-C₁₋₃-alkyl- groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen, H₂N—,            (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-C(O)—,            (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,            (C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,            C₃₋₅-cycloalkyl- and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,                (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl- and                C₁₋₆-alkyl- groups may optionally be substituted with 1                to 13 fluorine atoms.

In a further embodiment of the present invention

-   R² is selected from the group R^(2c) consisting of    -   H, C₁₋₈-alkyl-, C₃₋₇-cycloalkyl-, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,        phenyl, phenyl-C₁₋₃-alkyl-, C-linked heterocyclyl and        heterocyclyl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₈-alkyl-, C₃₋₇-cycloalkyl-,            C₃₋₇-cycloalkyl-C₁₋₃-alkyl-, phenyl, phenyl-C₁₋₃-alkyl-,            C-linked heterocyclyl and heterocyclyl-C₁₋₃-alkyl- groups            may optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of HO—,            oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,            cyano, halogen, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl-            and C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl- and                C₁₋₆-alkyl- groups may optionally be substituted with 1                to 13 fluorine atoms.

In a further embodiment of the present invention

-   R² is selected from the group R^(2d) consisting of    -   H, C₁₋₅-alkyl-, C₃₋₆-cycloalkyl-, C-linked heterocyclyl-, phenyl        and phenyl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₅-alkyl-, C₃₋₆-cycloalkyl-,            C-linked heterocyclyl-, phenyl and phenyl-C₁₋₃-alkyl-groups            may optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of HO—,            C₁₋₃-alkyl-O— and a saturated 4 to 6 membered monocyclic            ring containing one O atom,        -   wherein above mentioned C₁₋₅-alkyl-, C₃₋₆-cycloalkyl-,            C-linked heterocyclyl-, phenyl, phenyl-C₁₋₃-alkyl- and            C₁₋₃-alkyl-O— groups may optionally be substituted with 1 to            11 fluorine atoms.

In a further embodiment of the present invention

-   R² is selected from the group R^(2e) consisting of    -   H, C₁₋₅-alkyl-, C₁₋₃-alkyl-O—C₁₋₃-alkyl-, cyclopropyl, phenyl,

-   -   -   wherein above mentioned C₁₋₅-alkyl- and phenyl groups may            optionally be substituted with 1 to 3 fluoroatoms.

In a further embodiment of the present invention

-   R³ is selected from the group R^(3b) consisting of    -   H, C₁₋₈-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked        heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl-C₁₋₃-alkyl-,        heteroaryl-C₁₋₃-alkyl- and R⁴R⁵N—C₂₋₃-alkyl-,        -   wherein above mentioned C₁₋₈-alkyl-, carbocyclyl,            carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,            heterocyclyl-C₁₋₃-alkyl-, aryl-C₁₋₃-alkyl-, and            heteroaryl-C₁₋₃-alkyl-groups may optionally be substituted            with 1 to 3 substituents independently selected from the            group consisting of HO—, oxo, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen, H₂N—,            (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-C(O)—,            (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,            (C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and            C₁₋₆-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,                (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,                (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,                C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groups may                optionally be substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R³ is selected from the group R^(3c) consisting of    -   H, C₃₋₅-cycloalkyl and C₁₋₅-alkyl-,        -   wherein above mentioned C₃₋₅-cycloalkyl- and C₁₋₅-alkyl-            groups may optionally be substituted with 1 to 3            substituents independently selected from the group            consisting of HO—, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,            heterocyclyl-O— and C₁₋₄-alkyl-O—C₁₋₄-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O— and                C₁₋₄-alkyl-O—C₁₋₄-alkyl- groups may optionally be                substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R³ is selected from the group R^(3d) consisting of    -   H, and C₁₋₅-alkyl-,        -   wherein above mentioned C₁₋₅-alkyl- group may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of HO—, C₁₋₄-alkyl-O—,            C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, and            C₁₋₄-alkyl-O—C₁₋₄-alkyl-, and            -   wherein above mentioned C₁₋₄-alkyl-O—,                C₃₋₆-cycloalkyl-O—, heterocyclyl-O— and                C₁₋₄-alkyl-O—C₁₋₄-alkyl- groups may optionally be                substituted with 1 to 13 fluorine atoms.

In a further embodiment of the present invention

-   R³ is selected from the group R^(3e) consisting of    -   H and H₃C—.

In a further embodiment of the present invention

-   R⁴, R⁵ are selected independently of each other from the group    R^(4b)/R^(5b) consisting of    -   H, C₁₋₆-alkyl-, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,        C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, heterocyclyl,        heterocyclyl-C₁₋₆-alkyl-, aryl, aryl-C₁₋₃-alkyl-,        aryl-O—C₂₋₃-alkyl-, heteroaryl and heteroaryl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₆-alkyl-, C₃₋₇-cycloalkyl-,            C₃₋₇-cycloalkyl-C₁₋₃-alkyl-, C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-,            heterocyclyl or heterocyclyl-C₁₋₆-alkyl- groups may            optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of fluoro,            HO—, oxo, C₁₋₄-alkyl-O— which is optionally fluorinated with            1 to 9 fluorine atoms, HO—C₁₋₄-alkyl-,            C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl,            (C₁₋₃-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms,        -   wherein above mentioned aryl-, aryl-C₁₋₃-alkyl-,            aryl-O—C₂₋₃-alkyl-, heteroaryl- and heteroaryl-C₁₋₃-alkyl-            groups may optionally be substituted with 1 to 3            substituents independently selected from the group            consisting of C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—, cyano,            halogen, (C₁₋₄-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is            optionally fluorinated with 1 to 13 fluorine atoms, or    -   R^(4b) and R^(5b) form together with the nitrogen atom to which        they are attached a 4-12-membered mono-, bicyclic or bridged        ring system optionally containing one double bond and/or one        aromatic ring and optionally containing one additional        heteroatom selected from the group consisting of —O—, —N(R⁶)—,        -   wherein 2 geminal hydrogen atoms of the 4-12-membered mono-            or bicyclic ring may be replaced by a —(CH₂)₁₋₅— group and            -   wherein one —(CH₂)— group of the —(CH₂)₁₋₅— group may be                replaced by —O— or —N(R⁶)— and        -   wherein above mentioned 4-12-membered mono-, bicyclic or            bridged ring system may optionally be substituted with 1 or            2 substituents independently selected from the group            consisting of fluoro, aryl, heteroaryl, C₁₋₆-alkyl- which is            optionally fluorinated with 1 to 13 fluorine atoms,            heterocyclyl, HO—, oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—,            HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl-O—            and (R⁶)₂N—,            -   wherein the directly above mentioned aryl and heteroaryl                groups may optionally be substituted with 1 to 3                substituents independently selected from the group                consisting of C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,                cyano, halogen, (C₁₋₄-alkyl)₂N—C(O)— and C₁₋₆-alkyl-                which is optionally fluorinated with 1 to 13 fluorine                atoms.

In a further embodiment of the present invention

-   R⁴, R⁵ are selected independently of each other from the group    R^(4c)/R^(5c) consisting of    -   H, C₁₋₆-alkyl-, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,        C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, azetidinyl, pyrrolidinyl,        piperidinyl, azepanyl, oxetanyl, tetrahydrofuryl,        tetrahydropyranyl, oxepanyl, dioxepanyl, tetrahydrothiophenyl,        1-oxo-tetrahydrothiophenyl 1,1-dioxo-tetrahydrothiophenyl,        azetidinyl-C₁₋₃-alkyl-, pyrrolidinyl-C₁₋₃-alkyl-,        piperidinyl-C₁₋₃-alkyl-, piperazinyl-C₁₋₃-alkyl-,        oxetanyl-C₁₋₃-alkyl-, tetrahydrofuryl-C₁₋₃-alkyl-,        tetrahydropyranyl-C₁₋₃-alkyl-, phenyl, phenyl-C₁₋₃-alkyl-,        phenyl-O—C₂₋₃-alkyl-, triazolyl-C₁₋₃-alkyl-,        pyrazolyl-C₁₋₃-alkyl-, oxazolyl-C₁₋₃-alkyl-,        isoxazolyl-C₁₋₃-alkyl-, oxadiazolyl-C₁₋₃-alkyl-,        thiazolyl-C₁₋₃-alkyl-, pyridinyl-C₁₋₃-alkyl-,        pyrazinyl-C₁₋₃-alkyl-, pyridazinyl-C₁₋₃-alkyl-,        pyrimidinyl-C₁₋₃-alkyl-, triazinyl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₆-alkyl-, C₃₋₇-cycloalkyl,            C₃₋₇-cycloalkyl-C₁₋₃-alkyl-, C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-,            azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl,            tetrahydrofuryl, tetrahydropyranyl, oxepanyl, dioxepanyl,            tetrahydrothiophenyl, 1-oxo-tetrahydrothiophenyl            1,1-dioxo-tetrahydrothiophenyl, azetidinyl-C₁₋₃-alkyl-,            pyrrolidinyl-C₁₋₃-alkyl-, piperidinyl-C₁₋₃-alkyl-,            piperazinyl-C₁₋₃-alkyl-, oxetanyl-C₁₋₃-alkyl-,            tetrahydrofuryl-C₁₋₃-alkyl-, tetrahydropyranyl-C₁₋₃-alkyl-            or oxazepanyl-C₁₋₃-alkyl- groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of fluoro, HO—, oxo,            C₁₋₄-alkyl-O—, HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,            morpholinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl,            (C₁₋₃-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is optionally            fluorinated with 1 to 13 fluorine atoms,        -   wherein above mentioned phenyl-, phenyl-C₁₋₃-alkyl-,            phenyl-O—C₂₋₃-alkyl-, triazolyl-C₁₋₃-alkyl-,            pyrazolyl-C₁₋₃-alkyl-, oxazolyl-C₁₋₃-alkyl-,            isoxazolyl-C₁₋₃-alkyl-, oxadiazolyl-C₁₋₃-alkyl-,            thiazolyl-C₁₋₃-alkyl-, pyridinyl-C₁₋₃-alkyl-,            pyrazinyl-C₁₋₃-alkyl-, pyridazinyl-C₁₋₃-alkyl-,            pyrimidinyl-C₁₋₃-alkyl-, and triazinyl-C₁₋₃-alkyl- groups            may optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of            C₁₋₃-alkyl-, F₃C—, C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,            cyano and halogen, or    -   R^(4c) and R^(5c) form together with the nitrogen atom to which        they are attached a 4-11-membered mono-, bicyclic or bridged        ring system optionally containing one aromatic ring and        optionally one additional heteroatom selected from the group        consisting of —O—, —N(R⁶)—,        -   wherein 2 geminal hydrogen atoms of the 4-11-membered            saturated mono- or bicyclic ring may be replaced by a            —(CH₂)₁₋₅— group and            -   wherein one —(CH₂)— group of the —(CH₂)₁₋₅— group may be                replaced by —O— or —N(R⁶)— and        -   wherein above mentioned 4-11-membered mono-, bicyclic or            bridged ring system may optionally be substituted with 1 or            2 substituents independently selected from the group            consisting of fluoro, aryl, heteroaryl, C₁₋₆-alkyl- which is            optionally fluorinated with 1 to 13 fluorine atoms,            heterocyclyl, HO—, oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—,            HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl-O—,            (R⁶)₂N—;            -   wherein the directly above mentioned aryl and heteroaryl                groups may optionally be substituted with 1 to 3                substituents independently selected from the group                consisting of C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,                cyano, halogen, (C₁₋₄-alkyl)₂N—C(O)— and C₁₋₆-alkyl-                which is optionally fluorinated with 1 to 13 fluorine                atoms.

In a further embodiment of the present invention

-   R⁴, R⁵ are selected independently of each other from the group    R^(4d)/R^(5d) consisting of    -   H, C₁₋₆-alkyl-, C₃₋₇-cycloalkyl-, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,        C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, azetidinyl, pyrrolidinyl,        piperidinyl, azepanyl, oxetanyl, tetrahydrofuryl,        tetrahydropyranyl, oxepanyl, dioxepanyl, tetrahydrothiophenyl,        1-oxo-tetrahydrothiophenyl 1,1-dioxo-tetrahydrothiophenyl,        azetidinyl-C₁₋₃-alkyl-, pyrrolidinyl-C₁₋₃-alkyl-,        piperidinyl-C₁₋₃-alkyl-, piperazinyl-C₁₋₃-alkyl-,        oxetanyl-C₁₋₃-alkyl-, tetrahydrofuryl-C₁₋₃-alkyl-,        tetrahydropyranyl-C₁₋₃-alkyl-, phenyl, phenyl-C₁₋₃-alkyl-,        phenyl-O—C₂₋₃-alkyl-, triazolyl-C₁₋₃-alkyl-,        pyrazolyl-C₁₋₃-alkyl-, oxazolyl-C₁₋₃-alkyl-,        isoxazolyl-C₁₋₃-alkyl-, oxadiazolyl-C₁₋₃-alkyl-,        thiazolyl-C₁₋₃-alkyl-, pyridinyl-C₁₋₃-alkyl-,        pyrazinyl-C₁₋₃-alkyl-, pyridazinyl-C₁₋₃-alkyl-,        pyrimidinyl-C₁₋₃-alkyl-, triazinyl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₆-alkyl-, C₃₋₇-cycloalkyl,            C₃₋₇-cycloalkyl-C₁₋₃-alkyl-, C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-,            azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl,            tetrahydrofuryl, tetrahydropyranyl, oxepanyl, dioxepanyl,            tetrahydrothiophenyl, 1-oxo-tetrahydrothiophenyl            1,1-dioxo-tetrahydrothiophenyl, azetidinyl-C₁₋₃-alkyl-,            pyrrolidinyl-C₁₋₃-alkyl-, piperidinyl-C₁₋₃-alkyl-,            piperazinyl-C₁₋₃-alkyl-, oxetanyl-C₁₋₃-alkyl-,            tetrahydrofuryl-C₁₋₃-alkyl- or tetrahydropyranyl-C₁₋₃-alkyl-            groups may optionally be substituted with 1 to 3            substituents independently selected from the group            consisting of fluoro, HO—, oxo, C₁₋₄-alkyl-O—,            HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, oxetanyl,            tetrahydrofuryl, tetrahydropyranyl, and C₁₋₆-alkyl- which is            optionally fluorinated with 1 to 13 fluorine atoms,        -   wherein above mentioned phenyl-, phenyl-C₁₋₃-alkyl-,            phenyl-O—C₂₋₃-alkyl-, triazolyl-C₁₋₃-alkyl-,            pyrazolyl-C₁₋₃-alkyl-, oxazolyl-C₁₋₃-alkyl-,            isoxazolyl-C₁₋₃-alkyl-, oxadiazolyl-C₁₋₃-alkyl-,            thiazolyl-C₁₋₃-alkyl-, pyridinyl-C₁₋₃-alkyl-,            pyrazinyl-C₁₋₃-alkyl-, pyridazinyl-C₁₋₃-alkyl-            pyrimidinyl-C₁₋₃-alkyl- and triazinyl-C₁₋₃-alkyl- groups may            optionally be substituted with 1 to 3 substituents            independently selected from the group consisting of            C₁₋₃-alkyl-, F₃C—, C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,            cyano and halogen, or    -   R^(4d) and R^(5d) form together with the nitrogen atom to which        they are attached a ring system selected from the group        consisting of,

-   -   -   wherein 2 geminal hydrogen atoms of the above mentioned            mono- or bicyclic ring may be replaced by a —(CH₂)₃₋₅— group            and            -   wherein one —(CH₂)— group of the —(CH₂)₃₋₅— group may be                replaced by —O— or —N(R⁶)— and        -   wherein above mentioned mono- or bicyclic ring may            optionally be substituted with 1 or 2 substituents            independently selected from the group consisting of fluoro,            phenyl, C₁₋₆-alkyl- which is optionally fluorinated with 1            to 13 fluorine atoms, azetidinyl, pyrrolidinyl, piperidinyl,            azepanyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl,            oxepanyl, dioxepanyl, tetrahydrothiophenyl,            1-oxo-tetrahydrothiophenyl 1,1-dioxo-tetrahydrothiophenyl,            HO—, oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, HO—C₁₋₄-alkyl-,            C₁₋₄-alkyl-O—C₁₋₄-alkyl-, oxetanyl-O—, tetrahydrofuryl-O—,            tetrahydropyranyl-O— and (R⁶)₂N—            -   wherein the aforementioned phenyl groups may optionally                be substituted with 1 to 3 substituents independently                selected from the group consisting of F₃C—,                C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—, cyano, halogen,                and C₁₋₃-alkyl-.

In a further embodiment of the present invention

-   R⁴, R⁵ are selected independently of each other from the group    R^(4e)/R^(5e) consisting of    -   H, C₁₋₆-alkyl-, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,        C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, azetidinyl, pyrrolidinyl,        piperidinyl, azepanyl, oxetanyl, tetrahydrofuryl,        tetrahydropyranyl, oxepanyl, dioxepanyl, tetrahydrothiophenyl,        1-oxo-tetrahydrothiophenyl 1,1-dioxo-tetrahydrothiophenyl,        azetidinyl-C₁₋₃-alkyl-, pyrrolidinyl-C₁₋₃-alkyl-,        piperidinyl-C₁₋₃-alkyl-, piperazinyl-C₁₋₃-alkyl-,        oxetanyl-C₁₋₃-alkyl-, tetrahydrofuryl-C₁₋₃-alkyl-,        tetrahydropyranyl-C₁₋₃-alkyl-,        -   wherein above mentioned C₁₋₆-alkyl-, C₃₋₇-cycloalkyl,            C₃₋₇-cycloalkyl-C₁₋₃-alkyl-, C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-,            azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl,            tetrahydrofuryl, tetrahydropyranyl, oxepanyl, dioxepanyl,            tetrahydrothiophenyl, 1-oxo-tetrahydrothiophenyl            1,1-dioxo-tetrahydrothiophenyl, azetidinyl-C₁₋₃-alkyl-,            pyrrolidinyl-C₁₋₃-alkyl-, piperidinyl-C₁₋₃-alkyl-,            piperazinyl-C₁₋₃-alkyl-, oxetanyl-C₁₋₃-alkyl-,            tetrahydrofuryl-C₁₋₃-alkyl-,            tetrahydropyranyl-C₁₋₃-alkyl-groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of fluoro, HO—, oxo,            C₁₋₄-alkyl-O—, HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and            C₁₋₃-alkyl- which is optionally fluorinated with 1 to 7            fluorine atoms,        -   or    -   R^(4e) and R^(5e) form together with the nitrogen atom to which        they are attached a ring system selected from the group        consisting of

-   -   -   wherein above mentioned monocyclic rings may optionally be            substituted with 1 or 2 substituents independently selected            from the group consisting of fluoro, C₁₋₃-alkyl- which is            optionally fluorinated with 1 to 7 fluorine atoms, HO—, oxo,            C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, HO—C₁₋₄-alkyl- and            C₁₋₄-alkyl-O—C₁₋₄-alkyl-.

In a further embodiment of the present invention

-   R⁴, R⁵ are selected independently of each other from the group    R^(4f)/R^(5f) consisting of    -   H and C₁₋₅-alkyl- which is optionally fluorinated with 1 to 13        fluorine atoms.

In a further embodiment of the present invention

-   R⁶ is selected independently of each other from the group R^(6b)    consisting of    -   H, C₁₋₆-alkyl-, C₃₋₆-cycloalkyl, oxetanyl, tetrahydrofuryl,        tetrahydropyranyl, pyridinyl, pyrimidinyl, pyridazinyl,        pyrazinyl, triazinyl, thiazolyl, oxadiazolyl, oxazolyl, HC(O)—,        C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, phenyl-C(O)—,        C₁₋₄-alkyl-O—C(O)— and (C₁₋₄-alkyl)₂N—C(O)—,        -   wherein above mentioned C₁₋₆-alkyl-, C₃₋₆-cycloalkyl-,            C₁₋₆-alkyl-C(O)— and C₃₋₆-cycloalkyl-C(O)— groups may            optionally be substituted with 1-13 fluorine atoms,        -   wherein the aforementioned phenyl-C(O)—, pyridinyl,            pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl            oxadiazolyl and oxazolyl groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of C₁₋₄-alkyl-O—, F₃C—, F₃CO—,            F₂HCO—, FH₂CO—, cyano, halogen, and C₁₋₃-alkyl-.

In a further embodiment of the present invention

-   R⁶ is selected independently of each other from the group R^(ho)    consisting of    -   H and C₁₋₅-alkyl- which is optionally fluorinated with 1 to 13        fluorine atoms.

In a further embodiment of the present invention

-   R⁷ is selected from the group R^(7b) consisting of    -   H.

Each R^(1x), R^(2x), R^(3x), R^(4x), R^(5x), R^(6x), R^(7x), A^(x),B^(x), D^(x), and W^(x) represents a characterized, individualembodiment for the corresponding substituent as described above. Thusgiven the above definitions, preferred individual embodiments of thefirst aspect of the invention are fully characterized by the term(R^(1x), R^(2x), R^(3x), R^(4x), R^(5x), R^(6x), R^(7x), A^(x), B^(x),D^(x), and W^(x)), wherein for each index x an individual figure isgiven that ranges from “a” to the highest letter given above. Allindividual embodiments described by the term in parentheses with fullpermutation of the indices x, referring to the definitions above, shallbe comprised by the present invention.

The following Table 1 shows, exemplarily and in the order of increasingpreference from the first line to the last line, such embodiments E-1 toE-40 of the invention that are considered preferred. This means thatembodiment E-40, represented by the entries in the last row of Table 1,is the most preferred embodiment.

TABLE 1 Preferred embodiments E-1 to E-40 of the invention A^(x) B^(x)D^(x) W^(x) R^(1x) R^(2x) R^(3x) R^(4x)/R^(5x) R^(6x) R^(7x) E-1 A^(b)B^(b) D^(b) W^(a) R^(1b) R^(2b) R^(3b) R^(4b)/R^(5b) R^(6b) R^(7a) E-2A^(b) B^(b) D^(c) W^(a) R^(1b) R^(2b) R^(3b) R^(4b)/R^(5b) R^(6b) R^(7a)E-3 A^(b) B^(b) D^(d) W^(b) R^(1b) R^(2c) R^(3b) R^(4c)/R^(5c) R^(6b)R^(7a) E-4 A^(b) B^(b) D^(d) W^(b) R^(1b) R^(2c) R^(3b) R^(4d)/R^(5d)R^(6c) R^(7b) E-5 A^(b) B^(b) D^(d) W^(b) R^(1b) R^(2c) R^(3b)R^(4e)/R^(5e) — R^(7b) E-6 A^(b) B^(b) D^(d) W^(b) R^(1b) R^(2c) R^(3b)R^(4f)/R^(5f) — R^(7b) E-7 A^(c) B^(c) D^(c) W^(b) R^(1b) R^(2b) R^(3b)R^(4b)/R^(5b) R^(6b) R^(7a) E-8 A^(c) B^(c) D^(c) W^(b) R^(1b) R^(2b)R^(3b) R^(4c)/R^(5c) R^(6c) R^(7b) E-9 A^(c) B^(c) D^(c) W^(b) R^(1c)R^(2c) R^(3b) R^(4d)/R^(5d) R^(6c) R^(7a) E-10 A^(c) B^(c) D^(c) W^(b)R^(1c) R^(2c) R^(3b) R^(4e)/R^(5e) — R^(7b) E-11 A^(d) B^(c) D^(f) W^(b)R^(1c) R^(2c) R^(3c) — — R^(7b) E-12 A^(d) B^(c) D^(g) W^(b) R^(1c)R^(2c) R^(3c) — — R^(7b) E-13 A^(d) B^(c) D^(h) W^(b) R^(1c) R^(2c)R^(3c) — — R^(7b) E-14 A^(d) B^(c) D^(f) W^(b) R^(1d) R^(2c) R^(3c) — —R^(7b) E-15 A^(d) B^(c) D^(g) W^(b) R^(1e) R^(2d) R^(3d) — — R^(7b) E-16A^(d) B^(c) D^(h) W^(b) R^(1f) R^(2e) R^(3e) — — R^(7b) E-17 A^(e) B^(c)D^(f) W^(b) R^(1c) R^(2c) R^(3c) — — R^(7b) E-18 A^(e) B^(c) D^(g) W^(b)R^(1c) R^(2c) R^(3c) — — R^(7b) E-19 A^(e) B^(c) D^(h) W^(b) R^(1c)R^(2c) R^(3c) — — R^(7b) E-20 A^(e) B^(c) D^(f) W^(b) R^(1d) R^(2c)R^(3c) — — R^(7b) E-21 A^(e) B^(c) D^(g) W^(b) R^(1d) R^(2c) R^(3c) — —R^(7b) E-22 A^(e) B^(c) D^(h) W^(b) R^(1d) R^(2c) R^(3c) — — R^(7b) E-23A^(e) B^(c) D^(f) W^(b) R^(1e) R^(2c) R^(3c) — — R^(7b) E-24 A^(e) B^(c)D^(g) W^(b) R^(1e) R^(2c) R^(3c) — — R^(7b) E-25 A^(e) B^(c) D^(h) W^(b)R^(1e) R^(2c) R^(3c) — — R^(7b) E-26 A^(e) B^(c) D^(f) W^(b) R^(1f)R^(2c) R^(3c) — — R^(7b) E-27 A^(e) B^(c) D^(g) W^(b) R^(1f) R^(2c)R^(3c) — — R^(7b) E-28 A^(e) B^(c) D^(h) W^(b) R^(1f) R^(2c) R^(3c) — —R^(7b) E-29 A^(e) B^(c) D^(f) W^(b) R^(1f) R^(2d) R^(3c) — — R^(7b) E-30A^(e) B^(c) D^(g) W^(b) R^(1f) R^(2d) R^(3c) — — R^(7b) E-31 A^(e) B^(c)D^(h) W^(b) R^(1f) R^(2d) R^(3c) — — R^(7b) E-32 A^(e) B^(c) D^(f) W^(b)R^(1f) R^(2e) R^(3c) — — R^(7b) E-33 A^(e) B^(c) D^(f) W^(b) R^(1f)R^(2e) R^(3d) — — R^(7b) E-34 A^(e) B^(c) D^(f) W^(b) R^(1f) R^(2e)R^(3e) — — R^(7b) E-35 A^(e) B^(c) D^(g) W^(b) R^(1f) R^(2e) R^(3c) — —R^(7b) E-36 A^(e) B^(c) D^(g) W^(b) R^(1f) R^(2e) R^(3d) — — R^(7b) E-37A^(e) B^(c) D^(g) W^(b) R^(1f) R^(2e) R^(3e) — — R^(7b) E-38 A^(e) B^(c)D^(h) W^(b) R^(1f) R^(2e) R^(3c) — — R^(7b) E-39 A^(e) B^(c) D^(h) W^(b)R^(1f) R^(2e) R^(3d) — — R^(7b) E-40 A^(e) B^(c) D^(h) W^(b) R^(1f)R^(2e) R^(3e) — — R^(7b)the tautomers thereof, the stereoisomers thereof, the mixtures thereof,and the salts thereof.

Accordingly, for example E-40 covers compounds of formula I, wherein

-   A is selected from the group A^(e) consisting of

-   -   wherein above mentioned groups may optionally be substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen and C₁₋₃-alkyl- which is optionally        fluorinated with 1 to 7 fluorine atoms;

-   B is selected from the group B^(c) consisting of

-   -   wherein above mentioned phenyl- and pyridinyl- groups may        optionally be substituted with 1 or 2 substituents independently        selected from the group consisting of halogen, cyano,        C₁₋₃-alkyl- which is optionally fluorinated with 1 to 7 fluorine        atoms, and C₁₋₃-alkyl-O— which is optionally fluorinated with 1        to 7 fluorine atoms;

-   D is selected from the group D^(h) consisting of

-   W is selected from the group W^(b) consisting of    -   —(R⁷)N—;-   R¹ is selected from the group R^(1f) consisting of    -   H, C₁₋₄-alkyl-        -   wherein above mentioned C₁₋₈-alkyl-groups may optionally be            substituted with 1 to 3 substituents independently selected            from the group consisting of HO—, C₁₋₃-alkyl-O—, cyano, and            halogen;-   R² is selected from the group R^(ee) consisting of    -   H, C₁₋₅-alkyl-, C₁₋₃-alkyl-O—C₁₋₃-alkyl-, cyclopropyl, phenyl,

-   -   -   wherein above mentioned C₁₋₅-alkyl- and phenyl groups may            optionally be substituted with 1 to 3 fluoroatoms;

-   R³ is selected from the group R^(3e) consisting of    -   H and H₃C—;

-   R⁷ is selected from the group R^(7b) consisting of    -   H;        the tautomers thereof, the stereoisomers thereof, the mixtures        thereof, and the salts thereof.

Further preferred are the following compounds listed in table 2:

No. Structure I

II

III

IV

V

VI

VII

VIII

IX

X

XI

XII

XIII

XIV

XV

XVI

XVII

XVIII

XIX

XX

XXI

XXII

XXIII

XXIV

XXV

XXVI

XXVII

XXVIII

XXIX

XXX

XXXI

XXXII

XXXIII

XXXIV

XXXV

XXXVI

XXXVII

XXXVIII

XXXIX

XL

XLI

XLII

XLIII

XLIV

XLV

XLVI

XLVII

XLVIII

XLIX

L

LI

LII

LIII

LIV

LV

LVI

LVII

LVIII

LIX

LX

LXI

LXII

LXIII

LXIV

LXV

LXVI

Some terms used above and hereinafter to describe the compoundsaccording to the invention will now be defined more closely.

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to. In the groups,radicals, or moieties defined below, the number of carbon atoms is oftenspecified preceding the group, for example C₁₋₆-alkyl means an alkylgroup or radical having 1 to 6 carbon atoms. In general, for groupscomprising two or more subgroups, the last named subgroup is the radicalattachment point, for example, the substituent “aryl-C₁₋₃-alkyl-” meansan aryl group which is bound to a C₁₋₃-alkyl group, the latter of whichis bound to the core or to the group to which the substituent isattached.

Within the present invention, the term “core molecule” is defined by thefollowing structure:

In general, the attachment site of a given residue to another groupshall be variable, i.e. any capable atom, bearing hydrogens to bereplaced, within this residue may be the linking spot to the group beingattached, unless otherwise indicated.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The dotted lines in sub-formulas of substituent D indicate the spiroatom being part of the core molecule of formula (I) and the substituentD. For example, the substructure

of substituent D means that ring D is attached to the core molecule offormula (I) via the indicated carbon atom resulting in the followingstructure:

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, aceticacid, 2,2-dichloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like (also see Pharmaceuticalsalts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term “substituted” as used herein means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's viable valencenumber is not exceeded, and that the substitution results in a stablecompound.

The term “partially unsaturated” as used herein means that in thedesignated group or moiety 1, 2, or more, preferably 1 or 2, doublebonds are present. Preferably, as used herein, the term “partiallyunsaturated” does not cover fully unsaturated groups or moieties.

The term “C-linked heterocyclyl” as used herein means that theheterocyclyl group is connected to the core molecule according toformula I by a bond from a C-atom of the heterocyclyl ring.

The term “halogen” generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. The term C₂₋₅-alkenyl includes for example theradicals H₂C═CH—, H₂C═CH—CH₂—, H₃C—CH═CH—, H₂C═CH—CH₂—CH₂—,H₃C—CH═CH—CH₂—, H₃C—CH₂—CH═CH—, (H₃C)₂C═CH—, H₂C═CH—CH₂—CH₂—CH₂—,H₃C—CH═CH—CH₂—CH₂—, H₃C—CH₂—CH═CH—CH₂—, H₃C—CH₂—CH₂—CH═CH—,H₂C═CH—CH═CH—CH₂— and (H₃C)₂C═CH—CH₂—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. The term C₂₋₅-alkinyl includes for example theradicals HC≡C—, HC≡C—CH₂—, H₃C—C≡C—, HC≡C—CH₂—CH₂—, H₃C—C≡C—CH₂—,H₃C—CH₂—C≡C—, HC≡C—CH₂—CH₂—CH₂—, H₃C—C≡C—CH₂—CH₂—, H₃C—CH₂—C≡C—CH₂—,H₃C—CH₂—CH₂—C≡C— and (H₃C)₂CH—C≡C—.

The term “carbocyclyl” as used either alone or in combination withanother radical, means, if not mentioned otherwise, a mono- bi- ortricyclic ring structure consisting of 3 to 14 carbon atoms. The term,if not mentioned otherwise, refers to fully saturated, partiallysaturated and aromatic ring systems. The term “carbocycle” encompassesfused, bridged and spirocyclic systems.

Thus, the term “carbocyclyl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

The term “C_(3-n)-cycloalkyl”, wherein n is an integer from 4 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The term “heterocyclyl” means a saturated or unsaturated mono- orpolycyclic-ring systems which may contain aromatic rings containing oneor more heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1 or 2,consisting of, if not mentioned otherwise, 3 to 14 ring atoms whereinnone of the heteroatoms is part of an aromatic ring. The term“heterocycle” is intended to include all the possible isomeric forms.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

The term “heteroaryl” means a mono- or polycyclic-ring systemscontaining one or more heteroatoms selected from N, O or S(O)_(r),wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at leastone of the heteroatoms is part of aromatic ring. The term “heteroaryl”is intended to include all the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

The compounds according to the invention may be obtained using methodsof synthesis known in principle. Preferably, the compounds are obtainedby the following methods according to the invention which are describedin more detail hereinafter.

The following schemes shall illustrate a process to manufacture thecompounds of the present invention by way of example:

Scheme 1 illustrates the synthesis of 6-substituted2,4-dichloro-5-nitro-pyrimidines (VI) als intermediates for thesynthesis of dihydropteridinones (I):

In a first step 2,4,6-trichloro-pyrimidine (II) is reacted with Grignardreagents R¹—Mg—X (with X=Cl, Br, I, R¹) in an appropriate solvent liketetrahydrofurane in the presence of a Copper catalyst (e.g. Cu(I)iodide) to form 6-substituted 2,4-dichloro-pyrimidine derivatives (III).These compounds are converted in a second step to the corresponding1H-pyrimidine-2,4-diones (IV) by heating with aqueous mineral acid (e.g.hydrochloric acid). In a third step, nitration, e.g. by using a mixtureof sulfuric acid and nitric acid, leads to the corresponding5-nitro-1H-pyrimidine-2,4-diones (V). In a fourth step, these compoundsare heated with phosphorus oxychloride resulting in the formation of6-substituted 2,4-dichloro-5-nitro-pyrimidines (VI).

Scheme 2: In a first step 6-substituted 2,4-dichloro-5-nitro-pyrimidines(VI, see Scheme 1) are reacted with alpha amino acid esters (VII, Rpreferentially methyl, ethyl) using an appropriate solvent/base systemlike diethyl ether/water/potassium hydrogen carbonate oracetone/water/potassium carbonate ordichloromethane/N-ethyl-diisopropylamine to form2-chloro-5-nitro-pyrimidinyl esters (VIII). These intermediates arereduced in a second step, e.g. using iron in acetic acid to formdihydropteridinones IX after in situ cyclization. Subsequent alkylationusing an alkylating agent R²—X (with X=Cl, Br, I, Me—SO₂—O—, CF₃—SO₂—O—,4-Me-Ph-SO₂—O—) and a base, e.g. sodium hydride or potassium carbonatein suitable solvents like N-methylpyrrolidone or dimethylformamide,leads to 2-chloro-7,8-dihydro-5H-pteridin-6-ones (X, step 3). These2-chloro-7,8-dihydro-5H-pteridin-6-ones (X) are converted in a fourthstep into the final products (I) by heating with an amine A-B—W—H in thepresence of a suitable catalyst (e.g. p-toluenesulfonic acid in aceticacid) in a suitable solvent like 4-methyl-2-pentanol orN-methylpyrrolidone or dimethylsulfoxide to form the finaldihydropteridinones (I). Alternatively, dihydropteridinones (I) can beobtained by heating 2-chloro-7,8-dihydro-5H-pteridin-6-ones (X) with anamine A-B—W—H in the presence of a suitable catalyst (e.g. Pd(OAc)₂ orPd₂(dba)₃), a ligand (e.g. BINAP, dppf or Xantphos) and a base (e.g.cesium carbonate or potassium tert.-butoxide) in a suitable solvent liketetrahydrofurane or 1,4-dioxane.

Scheme 3: In a first step 6-substituted 2,4-dichloro-5-nitro-pyrimidines(VI, see Scheme 1) are reacted with alpha amino acid esters (XI, Rpreferentially methyl, ethyl) using an appropriate solvent/base systemlike diethyl ether/water/potassium hydrogen carbonate oracetone/water/potassium carbonate ordichloromethane/N-ethyl-diisopropylamine to form2-chloro-5-nitro-pyrimidinyl esters (XII). These intermediates arereduced in a second step, e.g. using iron in acetic acid to formdihydropteridinones XIII after in situ cyclization. Subsequentalkylation using an alkylating agent R²—X (with X=Cl, Br, I, Me—SO₂—O—,CF₃—SO₂—O—, 4-Me-Ph-SO₂—O—) and a base, e.g. sodium hydride or potassiumcarbonate in suitable solvents like N-methylpyrrolidone ordimethylformamide, leads to 2-chloro-7,8-dihydro-5H-pteridin-6-ones(XIV, step 3). A second alkylation using an alkylating agent R²—X (withX=Cl, Br, I, Me—SO₂—O—, CF₃—SO₂—O—, 4-Me-Ph-SO₂—O—) and a base, e.g.sodium hydride or potassium carbonate in suitable solvents likeN-methylpyrrolidone or dimethylformamide, leads to2-chloro-7,8-dihydro-5H-pteridin-6-ones (X, step 3). These2-chloro-7,8-dihydro-5H-pteridin-6-ones (X) are converted in a fourthstep into the final products (I) by heating with an amine A-B—W—H in thepresence of a suitable catalyst (e.g. p-toluenesulfonic acid in aceticacid) in a suitable solvent like 4-methyl-2-pentanol orN-methylpyrrolidone or dimethylsulfoxide to form the finaldihydropteridinones (I). Alternatively, dihydropteridinones (I) can beobtained by heating 2-chloro-7,8-dihydro-5H-pteridin-6-ones (X) with anamine A-B—W—H in the presence of a suitable catalyst (e.g. Pd(OAc)₂ orPd₂(dba)₃), a ligand (e.g. BINAP, dppf or Xantphos) and a base (e.g.cesium carbonate or potassium tert.-butoxide) in a suitable solvent liketetrahydrofurane or 1,4-dioxane.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

As already mentioned, the compounds of general formula I according tothe invention and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly as modulators ofγ-secretase.

Biological Examples

Screening for compounds which preferentially inhibit production of Aβ42vs. total Aβ was performed using H4 neuroglioma cells stably expressingthe human APP695 isoform grown in Dulbecco's Modified Eagles medium(DMEM) GlutaMAX supplemented with 10% Fetal Bovine Serum and 250 μg/mLZeocine. Cells were plated out to near confluency. The compounds to betested were received as 10 mM stocks in 100% DMSO. A dilution series wasinitially generated in 100% DMSO and then diluted 200-fold in cellculture media such that the tested concentration range was 30 μM to 0.1nM and the final DMSO concentration was 0.5%. The diluted compounds wereincubated with the cells for 22 hours in an incubator at 37° C. and 5%CO₂. Aβ42 as well as Aβ total levels were then measured post-incubationfrom the supernatant of the cells. Aβ42 levels were determined using aspecific electrochemiluminescence assay provided by Meso Scale Discovery(Catalog #L21CA-1) according to the manufacturer's protocol. Aβ totallevels were likewise determined using a specificelectrochemiluminescence assay provided by Meso Scale Discovery (Catalog#L21ZA-1) according to the manufacturer's protocol. To identifycompounds which preferentially inhibited Aβ42, the ratio Aβ totalIC₅₀/Aβ42 IC₅₀ was determined, where the higher the ratio, the morespecific the inhibition of Aβ42 over Aβ total.

The compounds of general formula I according to the invention forexample have IC₅₀ values below 30000 nM, particularly below 1000 nM,most preferably below 500 nM.

TABLE 3 Activity of the examples (Ex) compiled in the experimental part,based on Aβ₄₂ cellular IC₅₀ values in H4 neuroglioma cells (see above).Ratio Ratio IC₅₀ Aβ(total)/ IC₅₀ Aβ(total)/ Ex [μM] Aβ₄₂ Ex [μM] Aβ₄₂  10.12 >244  2 0.19 89  3 5.4 >6  4 0.29 101  5 3.2 >9  6 0.22 >136  70.095 >315  8 3.0 >10  9 0.30 >101 10 0.62 46 11 0.31 26 12 1.9 11 132.2 >13 14 1.4 >27 15 2.1 >15 16 0.18 88 17 0.094 65 18 0.30 145 190.28 >257 20 0.79 >90 21 0.22 114 22 3.3 >9 23 0.039 599 24 3.0 >10 250.29 91 26 0.35 46 27 0.27 >112 28 10.5 >3 29 0.27 39 30 0.10 96 31 0.1847 32 0.079 124 33 0.14 124 34 0.073 115 35 0.076 180 36 0.069 179 370.94 29  37a 0.060 307  37b 0.172 47  37c 0.116 75 38 0.41 >15 44 0.08550  37d 0.815 >36 40 0.485 >62  37f 0.145 55 45 0.058 >517  37g 0.196 5846 0.098 >306  37e 0.086 82 47 0.191 98  37k 0.12 88 48 0.389 22  37h0.123 85 49 0.095 69  37i 0.15 54 50 0.204 >147  37j 0.073 57 51 0.059126 39 0.078 91 52 0.11 61 41 1.22 >25 53 0.04 132 42 0.206 51 54 0.022116 43 0.123 237 55 0.076 103

Whereas γ-Secretase inhibitors simultaneously inhibit production of allAβ species, γ-Secretase modulators preferentially inhibit the productionof the neurotoxic Aβ42 species. In order to absolutely define thedescribed compounds as modulators of γ-Secretase as opposed to simplyinhibitors of γ-Secretase, measurements of not only Aβ42 but also Aβtotal are performed. When the ratio of Aβ total IC₅₀/Aβ42 IC₅₀ is >1,the compound preferentially inhibits Aβ42 production, therebydemonstrating that the compound is in fact a γ-Secretase modulator.

In view of their ability to modulate the activity of γ-secretase, thecompounds of general formula I according to the invention are suitablefor the treatment and/or preventative treatment of all those conditionsor diseases which may be affected by the formation of Aβ peptides.Therefore, compounds according to the invention are particularlysuitable for the prevention or treatment of diseases, particularlyDown's syndrome, Abeta-amyloid angiopathy, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, a disorder associated with cognitiveimpairment, MCI (“mild cognitive impairment”), Alzheimer's Disease,memory loss, attention deficit symptoms associated with Alzheimer'sdisease, neurodegeneration associated with Alzheimer's disease, diffuseLewy body type of Alzheimer's Disease, dementia of mixed vascularorigin, dementia of degenerative origin, pre-senile dementia, seniledementia, dementia associated with Parkinson's disease, progressivesupranuclear palsy or cortical basal degeneration, the dry form ofage-related macular degeneration and glaucoma.

Preferably the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of Alzheimer's Disease, the dry form ofage-related macular degeneration and/or MCI.

In particular, the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of Alzheimer's Disease and/or MCI.

In a further aspect of the present invention the present inventionrelates to methods for the treatment or prevention of above mentioneddiseases and conditions, which method comprises the administration of aneffective amount of a compound of general formula I to a human being.

The dose range of the compounds of general formula I applicable per dayis usually from 0.1 to 1000 mg, preferably from 1 to 500 mg by oralroute, in each case administered 1 to 4 times a day.

Each dosage unit may conveniently contain from 0.1 to 500 mg, preferably1 to 100 mg.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a pharmaceutically effective amount to bedelivered based upon patient's unique condition.

Suitable preparations for administering the compounds of formula I willbe apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives, powders,etc. The content of the pharmaceutically active compound(s) should be inthe range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% of thecomposition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers.

For this purpose, the compounds of formula I prepared according to theinvention may be formulated, optionally together with other activesubstances, together with one or more inert conventional carriers and/ordiluents, e.g. with corn starch, lactose, glucose, microcrystallinecellulose, magnesium stearate, citric acid, tartaric acid, water,polyvinylpyrrolidone, water/ethanol, water/glycerol, water/sorbitol,water/polyethylene glycol, propylene glycol, cetylstearyl alcohol,carboxymethylcellulose or fatty substances such as hard fat or suitablemixtures thereof.

The compounds according to the invention may also be used in conjunctionwith other active substances, particularly for the treatment and/orprevention of the diseases and conditions mentioned above. Other activesubstances which are suitable for such combinations include, forexample, BACE inhibitors; amyloid aggregation inhibitors (e.g.ELND-005); directly or indirectly acting neuroprotective and/ordisease-modifying substances; anti-oxidants (e.g. vitamin E orginkolide); anti-inflammatory substances (e.g. Cox inhibitors, NSAIDsadditionally or exclusively having Abeta lowering properties); HMG-CoAreductase inhibitors (statins); acetylcholinesterase inhibitors (e.g.,donepezil, rivastigmine, tacrine, galantamine); NMDA receptorantagonists (e.g. memantine); AMPA receptor agonists; AMPA receptorpositive modulators, AMPAkines, monoamine receptor reuptake inhibitors,substances modulating the concentration or release of neurotransmitters;substances inducing the secretion of growth hormone (e.g., ibutamorenmesylate and capromorelin); CB-1 receptor antagonists or inverseagonists; antibiotics (e.g., minocyclin or rifampicin); PDE2, PDE4,PDE5, PDE9, PDE10 inhibitors, GABAA receptor inverse agonists, GABAAreceptor antagonists, nicotinic receptor agonists or partial agonists orpositive modulators, alpha4beta2 nicotinic receptor agonists or partialagonists or positive modulators, alpha7 nicotinic receptor agonists orpartial agonists or positive modulators; histamine H3 antagonists, 5HT-4 agonists or partial agonists, 5HT-6 antagonists,alpha2-adrenoreceptor antagonists, calcium antagonists, muscarinicreceptor M1 agonists or partial agonists or positive modulators,muscarinic receptor M2 antagonists, muscarinic receptor M4 antagonists,metabotropic glutamate-receptor 5 positive modulators, glycinetransporter 1 inhibitors, antidepressants, such as citalopram,fluoxetine, paroxetine, sertraline and trazodone; anxiolytics, such aslorazepam and oxazepam; antiphychotics, such as aripiprazole, clozapine,haloperidol, olanzapine, quetiapine, risperidone and ziprasidone, andother substances that modulate receptors or enzymes in a manner suchthat the efficacy and/or safety of the compounds according to theinvention is increased and/or unwanted side effects are reduced. Thecompounds according to the invention may also be used in combinationwith immunotherapies (e.g., active immunisation with Abeta or partsthereof or passive immunisation with humanised anti-Abeta antibodies ornanobodies) for the treatment of the above-mentioned diseases andconditions.

The dosage for the combination partners mentioned above is usefully ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention or a physiologically acceptable saltthereof combined with at least one of the active substances describedabove as a combination partner, for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be affected by modulation ofγ-secretase. These are preferably Aβ-related pathologies, particularlyone of the diseases or conditions listed above, most particularlyAlzheimer's Disease and/or MCI.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; while ifthey are used at staggered times the two active substances are given tothe patient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one of the active substances described above as combinationpartners, optionally together with one or more inert carriers and/ordiluents.

The compound according to the invention, or a physiologically acceptablesalt thereof, and the additional active substance to be combinedtherewith may both be present together in one formulation, for example atablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Experimental Section

The following examples are intended to illustrate the invention, withoutrestricting its scope.

As a rule, melting points, IR, ¹H-NMR and/or mass spectra have beenobtained for the compounds prepared. Unless otherwise stated, Rf valueswere obtained using ready-made silica gel 60 F254 TLC plates (E. Merck,Darmstadt, item no. 1.05714) without chamber saturation. The ratiosgiven for the eluants refer to units by volume of the solvents inquestion. Chromatographic purification was done using silica gelsupplied by E. Merck, Darmstadt (Silica gel 60, 0.040-0.063 mm, item no.1.09385.2500).

The following abbreviations are used in the following examples:

ACN Acetonitrile

Boc t-butyloxycarbonyl-

CH Cyclohexane

DAD Diode array detection

DCM Dichloromethane

DIPEA N-Ethyl-diisopr opylamine

DMSO Dimethylsulphoxide DMF N,N-Dimethylformamide

EA Ethyl acetateESI Electrospray ionisation

h Hour(s)

HPLC High performance liquid chromatography

M Molar MeOH Methanol min Minute(s) mL Milliliters μL Microliters

mmol Millimoles

μmol Micromoles

MPLC Medium pressure liquid chromatographyMS Mass spectrometry

NMP N-Methyl-pyrrolidinone

Pd/C Palladium on charcoalPE Petroleum etherpsi pound-force per square inchRf Retention factorRt Retention timesat. saturatedtert. TertiaryTLC Thin layer chromatographyTFA Trifluoroacetic acid

THF Tetrahydrofurane

UPLC Ultra performance liquid chromatography

All references to brine refer to a saturated aqueous solution of sodiumchloride. Unless otherwise indicated, all temperatures are expressed in° C. (degrees Centigrade). All reactions are conducted not under aninert atmosphere at room temperature unless otherwise noted.

EXAMPLES HPLC/UPLC Methods Method A

Device: Waters Alliance with DAD and ESI-MS detector Column: WatersXBridge C18, 4.6 × 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rateTemperature [min] [H₂O, 0.10% TFA] [MeOH] [mL/min] [° C.] 0.0 95 5 4 601.6 0 100 4 60 1.85 0 100 4 60 1.9 95 5 4 60

Method B

Device: Waters Alliance with DAD and ESI-MS detector Column: WatersXBridge C18, 4.6 × 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rateTemperature [min] [H₂O, 0.10% NH₃] [MeOH] [mL/min] [° C.] 0.0 95 5 4 600.2 95 5 4 60 1.5 0 100 4 60 1.75 0 100 4 60

Method C

Device: Waters Acquity with DAD and ESI-MS detector Column: WatersXBridge BEH C18, 2.1 × 30 mm, 1.7 μm % Solvent B Time % Solvent A [MeOH,Flow rate Temperature [min] [H₂O, 0.13% TFA] 0.05% TFA] [mL/min] [° C.]0.0 99 1 1.3 60 0.05 99 1 1.3 60 1.05 0 100 1.3 60 1.2 0 100 1.3 60

Method D

Device: Waters Alliance with DAD and ESI-MS detector Column: WatersXBridge C18, 4.6 × 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rateTemperature [min] [H₂O, 0.1% TFA] [MeOH] [mL/min] [° C.] 0.0 95 5 4 601.6 0 100 4 60 1.85 0 100 4 60 1.9 95 5 4 60

Method E

Device: Waters Acquity with DAD and ESI-MS detector Column: Sunfire C18,2.1 × 20 mm, 2.5 μm Time % Solvent A % Solvent B Flow rate Temperature[min] [H₂O, 0.1% TFA] [MeOH] [mL/min] [° C.] 0.00 99 1 1.3 60 0.15 99 11.3 60 1.10 0 100 1.3 60 1.25 0 100 1.3 60

Method F

Device: Agilent 1200 with DAD and ESI-MS detector Column: XBridge C18, 3× 30 mm, 2.5 μm Time % Solvent A % Solvent B Flow rate Temperature [min][H2O, 0.1% NH4OH] [MeOH] [mL/min] [° C.] 0.0 95 5 1.9 60 0.20 95 5 1.960 1.55 0 100 1.9 60 1.60 0 100 2.4 60 1.80 0 100 2.4 60

Method G

Device: Waters Acquity with DAD and ESI-MS detector Column: XBridge C18,2.1 × 20 mm, 2.5 μm Time % Solvent A % Solvent B Flow rate Temperature[min] [H2O, 0.10% TFA] [MeOH] [mL/min] [° C.] 0.0 95 5 1.4 60 0.05 95 51.4 60 1.00 0 100 1.4 60 1.1 0 100 1.4 60

Method H

Device: Waters Alliance with DA- and MS-Detector Column: XBridge C18_4.6× 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rate Temperature [min][H2O, 0.1% NH3] [Acetonitrile] [mL/min] [° C.] 0.0 97 3 5 60 0.2 97 3 560 1.6 0 100 5 60 1.7 0 100 5 60

Method I

Device: Waters Acquity with DA- and MS-Detector Column: XBridge BEHC18_2.1 × 30 mm, 1.7 μm Time % Solvent A % Solvent B Flow rateTemperature [min] [H2O, 0.1% TFA] [Acetonitrile] [mL/min] [° C.] 0.0 991 1.6 60 0.02 99 1 1.6 60 1.0 0 100 1.6 60 1.1 0 100 1.6 60

Method J

Device: Waters Acquity with DA- and MS-Detector Column: Sunfire C18, 2.1× 30 mm, 2.5 μm Time % Solvent A % Solvent B Flow rate Temperature [min][H2O, 0.1% TFA] [Acetonitrile] [mL/min] [° C.] 0.0 99 1 1.5 60 0.02 99 11.5 60 1.0 0 100 1.5 60 1.1 0 100 1.5 60

Method K

Device: Agilent 1200 with DAD and ESI-MS detector Column: XBridge C18, 3× 30 mm, 2.5 μm Time % Solvent A % Solvent B Flow rate Temperature [min][H2O, 0.1% TFA] [Acetonitrile] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 973 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3.0 60 1.40 0 100 3.0 60

Method L

Device: Waters Alliance with DA- and MS-Detector Column: Sunfire C18,4.6 × 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rate Temperature[min] [H2O, 0.1% TFA] [Acetonitrile] [mL/min] [° C.] 0.0 97 3 5 60 0.297 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60

Method M

Device: Waters Alliance with DA- and MS-Detector Column: Sunfire C18,4.6 × 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rate Temperature[min] [H2O, 0.1% TFA] [Methanol] [mL/min] [° C.] 0.00 95 5 4 60 1.60 0100 4 60 1.85 0 100 4 60 1.90 95 5 4 60

Method N

Device: Waters Alliance with DA- and MS-Detector Column: XBridge C18,4.6 × 30 mm, 3.5 μm Time % Solvent A % Solvent B Flow rate Temperature[min] [H2O, 0.1% TFA] [Acetonitrile] [mL/min] [° C.] 0.0 97 3 5 60 0.297 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60

Method O

Device: Agilent 1200 with DAD and ESI-MS detector Column: XBridge C18, 3× 30 mm, 2.5 μm Time % Solvent A % Solvent B Flow rate Temperature [min][H2O, 0.1% NH₃] [Acetonitrile] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 973 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3.0 60 1.40 0 100 3.0 60

Method P

Device: Waters Acquity with DA- and MS-Detector Column: BEH C18, 2.1 ×30 mm, 1.7 μm Time % Solvent A % Solvent B Flow rate Temperature [min][H2O, 0.1% NH₃] [Acetonitrile] [mL/min] [° C.] 0.0 95.0 5.0 1.5 60 0.80.1 99.9 1.5 60 0.9 0.1 99.9 1.5 60

Intermediate A1

4-Amino-tetrahydro-pyran-4-carboxylic acid (2.00 g, 11.0 mmol) is addedat 0° C. in portions to a mixture of MeOH (15 mL) and thionylchloride(1.60 mL, 0.022 mmol). The reaction mixture is heated to reflux for 12h. After evaporation of the solvents diethyl ether is added and theprecipitate is filtered off yielding the product as the hydrochloridesalt.

MS (ESI⁺): m/z=160 [M+H]⁺

Intermediate A2-1

4-(Boc-amino)tetrahydropyran-4-carboxylic acid (1.96 g, 8.00 mmol) ismixed with N,N-dimethylformamide (15 mL) and sodium hydride (60% in oil,0.800 g, 20.0 mmol).

Then methyl iodide (1.49 mL, 24.0 mmol) is added and the reactionmixture is stirred for 12 h at room temperature. The precipitate isfiltered off. The filtrate is concentrated in vacuo. The residue isextracted with water and EA. The organic phase is dried over magnesiumsulfate and concentrated in vacuo to give the product as an oil.

MS (ESI⁺): m/z=274 [M+H]⁺

HPLC (Method A): Rt=1.13 min

Intermediate A2

Intermediate A2-1 (2.88 g, 10.6 mmol) is dissolved in dioxane (10 mL)and 4M HCl solution in dioxane (10.6 mL) is added. The mixture isstirred for 12 h at room temperature. After concentration in vacuodiethylether is added and the resulting precipitate is filtered off. Theproduct is obtained as hydrochloride salt.

MS (ESI⁺): m/z=174 [M+H]⁺

HPLC (Method A): Rt=0.25 min

Intermediate A3

Intermediate A3 is prepared with racemic3-amino-tetrahydrofuran-3-carboxylic acid in analogy to the preparationof intermediate A1. As no precipitate is observed after adding diethylether, the reaction mixture is concentrated in vacuo yielding theproduct as hydrochloride salt.

MS (ESI⁺): m/z=146 [M+H]⁺

HPLC (Method A): Rt=0.15 min

Intermediate A4-1

Intermediate A3 (4.10 g, 22.6 mmol) is mixed with tetrahydrofuran (100mL), triethyl amine (3.49 mL, 24.8 mmol) and di-tert-butyl-dicarbonate(5.67 g, 26.0 mmol) and stirred for 12 h at 60° C. The precipitate isfiltered off and the filtrate is concentrated in vacuo to give theproduct as an oil.

MS (ESI⁺): m/z=246 [M+H]⁺

HPLC (Method A): Rt=0.97 min

Intermediate A4-2

Intermediate A4-2 is prepared with intermediate A4-1 in analogy to thepreparation of intermediate A2-1.

MS (ESI⁺): m/z=260 [M+H]⁺

HPLC (Method A): Rt=1.10 min

Intermediate A4

Intermediate A4 (as hydrochloride salt) is prepared with intermediateA4-2 in analogy to the preparation of intermediate A2 usingtrifluoroacetic acid instead of HCl. The product is obtained astrifluoroacetate.

MS (ESI⁺): m/z=160 [M+H]⁺

Intermediate A5-1

KCN (2.71 g, 41.0 mmol) is added to a solution of [1,4]dioxepan-6-one(5.00 g, 41 mmol) and methylamine hydrochloride (2.819 g, 41 mmol) inmethanol (25 mL) and water (25 mL) at 0° C. The reaction mixture isstirred at 0° C. for 3 h, warmed to rt and stirred over night. Themixture is concentrated in vacuo. Standard work up yielded crude A5-1which is used in the following step without further purification.

Intermediate A5-1b

KCN (0.69 g, 10.5 mmol) is added to a solution of 3-oxepanone (1.00 g,8.76 mmol; WO 2010021680) and benzylamine hydrochloride (1.26 g, 8.76mmol) in methanol (10 mL) and water (10 mL) and the reaction mixture isstirred at room temperature for 16 h. The mixture is diluted with sat.sodium bicarbonate solution and EA. The organic layer is separated,dried over sodium sulfate, filtered and concentrated in vacuo to get theproduct without further purification.

TLC (silica gel, PE/EA 7/3): Rf=0.60

Intermediate A5-2

A5-1 (800 mg, 5.12 mmol) in concentrated aqueous HCl solution (15.0 mL)is heated to reflux over night. The reaction mixture is concentrated invacuo and used in the next step without further purification.

Intermediate A5-2b

A5-1b (500 mg, 2.17 mmol) in conc. aqueous HCl solution and acetic acidis heated to reflux for 24 h. The reaction mixture is concentrated invacuo and used in the next step without further purification.

TLC (silica gel, PE/EA 1/1): Rf=0.20

Intermediate A5

A5-2 (5.00 g, 29.0 mmol) in ethanolic HCl (35%, 125 mL) is refluxed overnight. The reaction mixture is concentrated and purified by columnchromatography (silica: eluent: DCM:MeOH 100:1).

TLC (DCM/MeOH 30:1): Rf=0.3

Intermediate A5b

A5-2b (4.00 g, 16.0 mmol) in methanolic HCl (6 mol/L) is refluxed overnight. The reaction mixture is concentrated and the residue is dissolvedin water and neutralized with sat. sodium bicarbonate solution and thenextracted with EA. The combined organic layers are dried over sodiumsulfate, filtered and concentrated in vacuo to give the product.

TLC (silica gel, PE/EA 8/2): Rf=0.60

Intermediate A6-1

Intermediate A6-1 is prepared with2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalene-2-carboxylicacid in analogy to the preparation of intermediate A4-2.

HPLC (Method A): Rt=1.5 min

Intermediate A6

Intermediate A6-2a is prepared with intermediate 18a in analogy to thepreparation of intermediate A4.

HPLC (Method A): Rt=0.75 min

Intermediate A7

Intermediate A5b (2.40 g, 8.66 mmol) in methanol is hydrogenated (H₂atmosphere, 50 psi) with Pd/C (10%) at 30° C. The reaction mixture isfiltered and concentrated in vacuo to give the product without furtherpurification.

Intermediate A8-1

Intermediate A8-1 is prepared from dihydrofuran-3(2H)-one in analogy tothe preparation of intermediate A5-1b.

Intermediate A8

Intermediate A8 is prepared from intermediate A8-1 and n-butanole inanalogy to the preparation of intermediate A5-2b.

Intermediate A9-1

To a solution of 3-dibenzyl-amino-oxetane-3-carboxylic acid (1.50 g,5.045 mmol; WO 2010097372) in 30 mL ACN and 3 mL methanol,trimethylsilyldiazomethane in hexane (2 M, 3.03 mL, 6.054 mmol) is addeddropwise under cooling. The reaction mixture is stirred at roomtemperature for 1.5 h. To the reaction mixture conc. acetic acid (360μL) is added and evaporated. The residue is treated with sodiumhydroxide solution (1 mol/L) and extracted with DCM. The organic layeris concentrated in vacuo to give the product.

MS (ESI⁺): m/z=312 [M+H]⁺

HPLC (Method A): Rt=1.54 min.

Intermediate A9

Intermediate A9-1 (1.55 g, 4.978 mmol) in 75 mL methanol is hydrogenated(H₂ atmosphere, 50 psi) with Pd/C (10%) at room temperature for 9 h. Thereaction mixture is filtered and concentrated in vacuo to give theproduct without further purification.

MS (ESI⁺): m/z=132 [M+H]⁺

HPLC (Method A): Rt=0.13 min.

Intermediate A10

Intermediate A10-1 is prepared from 2-amino-2-norbornanecarboxylic acidin analogy to the preparation of intermediate A1.

MS (ESI⁺): m/z=170 [M+H]⁺

Intermediate A11-1

Intermediate A11-1 is prepared from Boc-1-aminocyclopentane-1-carboxylicacid in analogy to the preparation of intermediate A9-1.

MS (ESI⁺): m/z=244 [M+H]⁺

Intermediate A11-2

To intermediate A11-1 (1.429 g, 5.573 mmol) in DMF (20 mL) sodiumhydride (60% in oil, 0.470 g, 11.747 mmol) and methyl iodide (0.548 mL,8.810 mmol) are added and the reaction mixture is stirred at roomtemperature for 12 h. To the reaction mixture water is added andextracted with EA. The combined organic layers are washed with sat.sodium chloride solution, dried, filtered and concentrated in vacuo togive the product.

MS (ESI⁺): m/z=258 [M+H]⁺

Intermediate A11

To intermediate A11-2 (1.174 g, 4.562 mmol) hydrochloride acid (4 mol/Lin dioxane, 4.562 mL, 18.249 mmol) is added and the reaction mixture isstirred at room temperature for 12 h. The reaction mixture isconcentrated in vacuo to give the product as hydrochloride salt.

MS (ESI⁺): m/z=158 [M+H]⁺

Intermediate B1-1

2,4,6-trichloropyrimidine (14.0 mL, 116 mmol) and copper (I) iodide(2.21 g, 11.6 mmol) are mixed under argon with THF (200 mL). At 0° C.ethylmagnesium bromide (116 mL, 116 mmol, 1M in THF) is added slowly andthe reaction mixture is stirred for 2 h at 0° C., heated to roomtemperature and stirred for further 12 h. The reaction mixture isquenched with sat. ammonium chloride solution and extracted withtert.-butylmethyl ether. The organic phase is dried and concentrated invacuo. The product is obtained after purification by columnchromatography (silica, eluent: CH:EA 97:3).

MS (ESI⁺): m/z=177/179/181 (2Cl) [M+H]⁺

HPLC (Method B): Rt=1.15 min.

Intermediate B1-2

Intermediate B1-1 (19.22 g, 108.6 mmol) is mixed with HCl (75.0 mL, 32%in water) and heated to reflux for 2 h. The reaction mixture isconcentrated in vacuo and freeze dried to yield the product that is usedfor the next step without further purification.

MS (ESI⁺): m/z=141 [M+H]⁺

HPLC (Method B): Rt=0.38 min

Intermediate B1-3

Intermediate B1-2 (14.5 g, 103 mmol) is mixed with concentrated sulfuricacid (150 mL) at 0° C. Nitric acid (9.88 mL, 155 mmol; 65% in water) isadded slowly and the reaction mixture is stirred for 1 h at 0° C. andfor 12 h at room temperature. The reaction mixture is poured on ice andstirred for 2 h. The precipitate is filtered off and washed with waterto yield the product that is used for the next step without furtherpurification.

MS (ESI⁺): m/z=186 [M+H]⁺

HPLC (Method B): Rt=0.52 min.

Intermediate B1

Phosphorus oxychloride (50 mL) is mixed with N,N-diethylaniline (12.8mL, 81 mmol). Intermediate B1-3 (11.5 g, 62.1 mmol) is added at roomtemperature and stirred for 20 min, followed by heating to reflux for 2h. After cooling to room temperature the reaction mixture is poured intoice water. The precipitate is filtered off and purified by columnchromatography (silica, DCM/MeOH 99:1) to yield the product.

MS (ESI⁺): m/z=220/222/224 (2Cl) [M−H]⁻

HPLC (Method B): Rt=1.43 min.

Intermediate B2

Intermediate B2 was prepared in analogy to intermediate B1 starting with2,4,6-trichloropyrimidine and 2-methyl-propylmagnesium bromide.

HPLC (Method B): Rt=1.56 min.

Intermediate B3

Intermediate B3 was prepared in analogy to intermediate B1 starting with2,4-dihydroxy-5-nitro-6-(trifluoromethyl)pyrimidine.

HPLC (Method K): Rt=0.92 min.

Intermediate B4-1

To a solution of 4-bromo-2,6-dimethoxy-pyrimidine (6.80 g, 27.94 mmol)in THF (190 mL) and diethylether (190 mL) n-butyllithium (in hexane/THF,2.01 g, 30.74 mmol) is added dropwise with stirring at −78° C. After 4min ethyl trifluoroacetate (4.46 g, 30.74 mmol) in THF (50 mL) is addeddropwise at −78° C. The reaction mixture is stirred for 30 min at −78°C. and then the reaction is allowed to warm to room temperature slowlyand stirred over night at room temperature. To the reaction mixture 1 NHCl solution is added. The resulting mixture is extracted with EA andwashed with sat. sodium chloride solution and water. The organic phaseis dried over sodium sulfate, filtered and the solvent is evaporated invacuo. The residue is purified by flash column chromatography (silicagel, PE/EA=8/2) to give the product.

MS (ESI⁺): m/z=255 [M+H]⁺

TLC (silica gel, PE/EA 3/1): Rf=0.20

Intermediate B4-2

To a solution of intermediate B4-1 (5.90 g, 20.89 mmol) in MeOH (100 mL)in an ice water bath sodium borohydride (7.94 g, 208.92 mmol) is added.The mixture is stirred at room temperature for 2 h. Aq. ammoniumchloride solution is added and the mixture is extracted with chloroform.The combined organic layers are dried over MgSO₄, filtered andconcentrated in vacuo to give the product which is used in the next stepwithout further purification.

MS (ESI⁺): m/z=239 [M+H]⁺

TLC (silica gel, PE/EA 3/1): Rf=0.40

Intermediate B4-3

To a solution of intermediate B4-2 (1.00 g, 3.78 mmol) anddimethylaminopyridine (1.41 g, 11.34 mmol) in DCM (100 mL) phenylchlorothioformate (1.33 g, 7.76 mmo) is added dropwise at 0° C. Then themixture is stirred at room temperature for 2 h. To the reaction aq.sodium chloride solution is added and the organic layer is separated,dried over MgSO₄, filtered and concentrated in vacuo to give the productwhich is used in the next step without further purification.

MS (ESI⁺): m/z=375 [M+H]⁺

TLC (silica gel, PE/EA 10/1): Rf=0.80

Intermediate B4-4

To a solution of intermediate B4-3 (12.58 g, 30.25 mmol) and2,2′-azobis(isobutyronitrile) (1.03 g, 6.05 mmol) in toluene (200 mL)tri-n-butyltin hydride (35.93 g, 120.98 mmo) is added at roomtemperature and then the mixture is stirred under reflux for 2 h.Afterwards the solvent is removed in vacuo. The residue is purified byflash column chromatography (silica gel, PE/EA=9/1) to give the product.

MS (ESI⁺): m/z=223 [M+H]⁺

TLC (silica gel, PE/EA 10/1): Rf=0.60

Intermediate B4-5

Intermediate B4-4 (1.00 g, 4.501 mmol) is added to conc. HCl (15 mL) andrefluxed for 12 h. The reaction mixture is extracted with DCM. Theaqueous layer is concentrated in vacuo to give the product which is usedin the next step without further purification.

MS (ESI⁺): m/z=195 [M+H]⁺

TLC (silica gel, PE/EA 10/1): Rf=0.50

Intermediate B4-6

Intermediate B4-5 (0.340 g, 1.576 mmol) is dissolved in conc. H₂SO₄,then fuming HNO₃ is added while keeping the temperature below 5° C. Thereaction is stirred at 0-5° C. for 2 h. Then the reaction is warmed toroom temperature slowly and stirred over night.

The solution is poured into ice water (50 mL) and the aqueous phase isextracted with EA. The combined organic layers are concentrated in vacuoto give the crude product which was purified by flash columnchromatography (silica gel, EA) to give the product.

MS (ESI⁺): m/z=240 [M+H]⁺

Intermediate B4

Intermediate B4-6 (1.00 g, 4.18 mmol) and phosphorus oxychloride (10 mL)is stirred at 145° C. for 3 h in a microwave oven. Afterwards thereaction mixture is concentrated in vacuo to give the product.

HPLC (Method J): Rt=0.67 min

Intermediate C1

Intermediate A2 (500 mg, 2.39 mmol) is mixed with water (20 mL). Asolution of 2,4-dichloro-5-nitropyrimidin (463 mg, 2.39 mmol) in diethylether (20 mL) is added dropwise. Potassium bicarbonate (506 mg, 5.01mmol) is added and the reaction mixture is stirred for 12 h at roomtemperature.

After standard workup the resulting residue is purified by columnchromatography (silica, heptane:EE 100:0 to 76:24) to give the productas a solid.

MS (ESI⁺): m/z=331/333 (Cl) [M+H]⁺

HPLC (Method E): Rt=0.71 min

The following intermediates were prepared in an analogous manner tointermediate C1:

Structure Starting materials Mass signal(s) R_(f) Value or R_(t) Nr.Comment C2

2,4-dichloro-5- nitropyrimidin and A1 (M + H)⁺ = 317/319 (Cl) 1.03 min(Method D) C3

2,4-dichloro-5- nitropyrimidin and A3 (M + H)⁺ = 303/305 (Cl) 0.67 min(Method E) C4

2,4-dichloro-5- nitropyrimidin and A4 (M + H)⁺ = 317/319 (Cl) 0.69 min(Method E) C5

2,4-dichloro-5-nitro-6- methylpyrimidin and A2 (M + H)⁺ = 345/347 (Cl)0.81 min (Method E) C6

A3 and B1 (M + H)⁺ = 331/333 (Cl) 0.81 min (Method E) C7

A3 and B2 (M + H)⁺ = 359/361 (Cl) 0.92 min (Method E) C8

2,4-dichloro-5- nitropyrimidin and A5 (M + H)⁺ = 361/363 (Cl) 0.76 min(Method E) C9

2,4-dichloro-5- nitropyrimidin and A6 (M + H)⁺ = 377/379 (Cl) 1.46 min(Method A) C10

A1 and B3 (M + H)⁺ = 385/387 (Cl) 0.64 min (Method I) C11

B1 and 1-amino- cyclopropan-1- carboxylic acid ethylester HCl (M + H)⁺ =315/317 (Cl) 1.25 min (Method L) C13

A7 and 2,4-dichloro-5- nitro-pyrimidine (M + H)⁺ = 331/333 (Cl) 1.11 min(Method N) C15

A9 and 2,4-dichloro-5- nitro-pyrimidine (M − H)⁻ = 287/289 (Cl) 0.77 min(Method H) C16

4-oxepanecarboxylic acid-4-amino-methyl ester (WO 2011053948) and 2,4-dichloro-5-nitro- pyrimidine (M − H)⁻ = 331/333 (Cl) 0.51 min (Method I)C17

methyl 1- (methylamino)cyclo- propane-1-carboxylate and 2,4-dichloro-5-nitro-pyrimidine (M − H)⁻ = 287/289 (Cl) 0.57 min (Method J) C18

A10 and 2,4-dichloro-5- nitro-pyrimidine (M − H)⁻ = 327/329 (Cl) 1.26min (Method L) C19

A11 and 2,4-dichloro-5- nitro-pyrimidine (M + H)⁺ = 315/317 (Cl) 0.68min (Method J) C20

B4 and 1-amino- cyclopropane-1- carboxylic acid ethyl ester HCl (M + H)⁺= 369/371 (Cl) 0.70 min (Method J)

Intermediate C20-2

A solution of intermediate A3 (455 mg, 2.255 mmol) and DIPEA (1.156 mL,6.676 mmol) in 20 mL DCM is added dropwise to2,6-dichloro-5-nitro-pyrimidine-4-carboxylic acid methyl esterhydrochloride (600 mg, 2.255 mmol) in 40 mL DCM at −70° C. and stirringis continued at −70° C. for 1 h and at room temperature for 2 h. To thereaction mixture 60 mL potassium bicarbonate solution (10%) is added andthe layers are separated. The organic layer is concentrated in vacuo andthe residue is purified by preparative HPLC (eluent A: water+0.15% TFA,eluent B: ACN) to give the product.

HPLC (Method N): Rt=1.10 min

Intermediate C20-3

To a solution of cyclobutanecarboxylic acid 1-amino-methyl esterhydrochloride (10.0 g, 60.38 mmol; WO 2009146347) and potassiumcarbonate (301.9 mL, 120.76 mmol) in THF (300 mL) a solution of2,4-dichloro-5-nitro-pyrimidine (11.71 g, 60.38 mmol) in THF (50 mL) isadded dropwise at 0° C. The resulting mixture was stirred at thistemperature for 2 h. The mixture was diluted with DCM. The organic layerwas separated, washed with water, dried over Na2SO4 and concentrated invacuo. The crude product is purified by column chromatography on silicagel (PE/EA=50/1) to give the product.

MS (ESI⁺): m/z=287/289 (Cl) [M+H]⁺

TLC (silica gel, PE/EA=5/1): Rf=0.60

Intermediate C20-4

2,4-Dichloro-5-nitrol-pyrimidine (21.31 g, 109.9 mmol) in THF (200 mL)is added to the mixture of 1-amino-cyclopropylcarboxylic acid methylester (11.50 g, 13.03 mmol) and potassium carbonate (13.81 g, 99.88mmol) in THF (200 mL) and H2O (200 mL) at 0° C. Afterwards the mixtureis stirred at room temperature overnight.

The solvent is removed in vacuo and the resulting oil was purified by aflash column chromatography (silica gel, PE/EA=5/1) to afford theproduct.

TLC (silica gel, PE/EA=5/1): Rf=0.60

Intermediate D1

Intermediate C2 (1.48 g, 2.34 mmol) is mixed with acetic acid (11.4 mL,0.20 mmol) and heated to 60° C. Iron filings (639 mg, 11.4 mmol) areadded in portions and the reaction mixture is stirred at 70° C. for 1 hand filtered then over celite and activated carbon. The filtrate isconcentrated in vacuo. The residue is purified by preparative HPLC(eluent A: water+0.13% TFA, eluent B: MeOH) to give the product as asolid.

MS (ESI⁺): m/z=255/257 (Cl) [M+H]⁺

HPLC (Method A): Rt=0.65 min

The following intermediates were prepared in an analogous manner tointermediate D1:

Structure Starting materials Mass signal(s) R_(f) Value or R_(t) Nr.Comment D2

C1 (M + H)⁺ = 317/319 (Cl) 0.99 min (Method B) D3

C3 (M + H)⁺ = 241/243 (Cl) 0.98 min (Method B) D4

C4 (M + H)⁺ = 255/257 (Cl) 0.84 min (Method B) D5

C5 (M + H)⁺ = 283/285 (Cl) 0.96 min (Method B) D6

C6 (M + H)⁺ = 269/271 (Cl) 0.85 min (Method B) D7

C7 (M + H)⁺ = 297/299 (Cl) 1.11 min (Method B) D8

C8 (M + H)⁺ = 285/287 (Cl) 0.88 min (Method B) D9

C9 (M + H)⁺ = 315/317 (Cl) 1.39 min (Method A) D11

C13 (M + H)⁺ = 269/271 (Cl) 0.73 min (Method N) D13

C20-3 (M + H)⁺ = 225/227 (Cl) Rf = 0.40 (TLC: silica gel, DCM/MeOH =20/1) D14

C20-4 (M + H)⁺ = 211/213 (Cl) Rf = 0.40 (TLC: silica gel, DCM/MeOH =20/1) D15

C20-3 (M + H)⁺ = 225/227 (Cl) Rf = 0.40 (TLC: silica gel, DCM/MeOH =20/1) D16

C18 (M + H)⁺ = 265/267 (Cl) 0.81 min (Method H) D17

C19 (M + H)⁺ = 253/255 (Cl) 0.86 min (Method H) D18

C20 (M + H)⁺ = 293/295 (Cl) 0.65 min (Method H)

Intermediate D18-1

Intermediate C10 (0.52 g, 1.35 mmol) in methanol is hydrogenated (H₂atmosphere, 50 psi) with raney nickel at 60° C. for 17 h. The reactionmixture is heated under reflux for 4 h. The mixture is evaporated togive the product.

MS (ESI⁺): m/z=323/325 (Cl) [M+H]⁺

HPLC (Method I): Rt=0.44 min

The following intermediates were prepared in an analogous manner tointermediate D18-1:

Structure Starting materials Mass signal(s) R_(f) Value or R_(t) Nr.Comment D18- 2

C20-2 (M + H)⁺ = 313/315 (Cl) 0.79 min (Method N) D18- 3

C15 (M + H)⁺ = 227/229 (Cl) 0.16 min (Method O) D18- 4

C16 (M + H)⁺ = 269/271 (Cl) 0.35 min (Method J) D18- 5

C17 (M + H)⁺ = 225/227 (Cl) 0.69 min (Method H)

Intermediate E1

Intermediate D2 (500 mg, 1.96 mmol) is mixed with N,N-dimethylformamide(15 mL) and sodium hydride (60% in oil, 196 mg, 4.91 mmol) is added.Methyl iodide (0.306 mL, 4.91 mmol) is added and the reaction mixture isstirred for 12 h at room temperature. The solvent is evaporated and theresidue is extracted with ethyl acetate and water. The organic phase isdried over magnesium sulfate and concentrated in vacuo to give theproduct as an oil.

MS (ESI⁺): m/z=283/285 (Cl) [M+H]⁺

HPLC (Method A): Rt=0.96 min

The following intermediates were prepared in an analogous manner tointermediate E1:

Structure Starting materials Mass signal(s) R_(f) Value or R_(t) Nr.Comment E1b

D18-1 (M + H)⁺ = 351/353 (Cl) 0.86 min (Method O) E1c

C11 (M + H)⁺ = 267/269 (Cl) 1.02 min (Method L) E1e

D13 (M + H)⁺ = 253/255 (Cl) Rf = 0.40 (TLC: silica gel, PE/EA = 1/1) E1f

D18 (M + H)⁺ = 321/323 (Cl) 0.60 min (Method J)

Intermediate E2

Intermediate D5 (28.0 mg, 0.10 mmol) is dissolved in DMF (2 mL).Potassium carbonate (27.4 mg, 0.20 mmol) and methyl iodide (4.40 μL,0.12 mmol) are added and the resulting mixture is stirred at roomtemperature for 2 h. The solvent is evaporated and the residue isextracted with ethyl acetate and water. The organic phase is dried overmagnesium sulfate and concentrated in vacuo to give the product as asolid.

MS (ESI⁺): m/z=297/299 (Cl) [M+H]⁺

HPLC (Method E): Rt=0.70 min

The following intermediates were prepared in an analogous manner tointermediate E2.

Starting Structure materials Mass signal(s) R_(f) Value or R_(t) Nr.Comment E3

D4 and methyl iodide (M + H)⁺ = 269/271 (Cl) 0.90 min (Method D) E4

D2 and 2- bromoethyl- methylether (M + H)⁺ = 327/329 (Cl) 0.55 min(Method G) Purification with preparative HPLC, obtained astrifluoroacetate salt. E5

D4 and 2- bromoethyl- methylether (M + H)⁺ = 313/315 (Cl) 1.10 min(Method E) Purification with preparative HPLC, obtained astrifluoroacetate salt. E6

D2 and 1- iodopropane (M + H)⁺ = 311/313 (Cl) 0.77 min (Method E)Purification with preparative HPLC, obtained as trifluoroacetate salt.E7

D3 and methyliodide (M + H)⁺ = 255/257 (Cl) 0.52 min (Method E)Purification with preparative HPLC, obtained as trifluoroacetate salt E8

D4 and 3- iodooxetane (M + H)⁺ = 311/313 (Cl) 0.94 min (Method B) Heatedover night at 100° C.; Purification with preparative HPLC. E9

D3 and 4- (iodomethyl)- tetrahydro- pyrane (M + H)⁺ = 339/341 (Cl) 0.63min (Method E) Purification with preparative HPLC. E10

D3 and 4- (iodomethyl)- tetrahydro- pyrane (M + H)⁺ = 437/439 (Cl) 0.80min (Method E) Purification with preparative HPLC. E11

D4 and 2- iodopropane (M + H)⁺ = 297/299 (Cl) 0.75 min (Method E) Heatedin a pressure tube over night at 100° C.; Purification with preparativeHPLC. E12

E9 and methyliodide (M + H)⁺ = 353/355 (Cl) 0.74 min (Method E) Heatedin a pressure tube over night at 100° C.; Purification with preparativeHPLC. E13

D8 and methyliodide (M + H)⁺ = 299/301 (Cl) 0.67 min (Method E) E14

D3 and 3- iodooxetane (M + H)⁺ = 297/299 (Cl) 0.74 min (Method B) Heatedover night at 100° C.; Purification with preparative HPLC. E15

D3 and 1- bromo-3- methyl- butane (M + H)⁺ = 311/313 (Cl) 0.83 min(Method E) Purification with preparative HPLC. E16

D7 and methyliodide (M + H)⁺ = 311/313 (Cl) 0.76 min (Method E)Purification with preparative HPLC. E17

E16 and 2- bromoethyl- methylether (M + H)⁺ = 369/371 (Cl) 0.90 min(Method E) Purification with preparative HPLC. E18

D7 and methyliodide (M + H)⁺ = 325/327 (Cl) 0.87 min (Method E)Purification with preparative HPLC. E19

D6 and methyliodide (M + H)⁺ = 297/299 (Cl) 0.74 min (Method E)Purification with preparative HPLC. E20

D9 and methyliodide (M + H)⁺ = 329/331 (Cl) 1.43 min (Method A)Purification with preparative HPLC. E20a

E22 and methyliodide (M + H)⁺ = 309/311 (Cl) 0.52 min (Method J)Purification with preparative HPLC. E20b

E23 and methyliodide (M + H)⁺ = 381/383 (Cl) 0.64 min (Method J)Purification with preparative HPLC. E20c

D11 and methyliodide (M + H)⁺ = 297/299 (Cl) 1.02 min (Method H)Purification with preparative HPLC. E20e

D18-2 and methyliodide (M + H)⁺ = 341/343 (Cl) 1.24 min (Method N)Purification with preparative HPLC. E20f

D18-3 and methyliodide (M + H)⁺ = 255/257 (Cl) 0.66 min (Method H)Purification with preparative HPLC. E20g

D18-4 and methyliodide (M + H)⁺ = 297/299 (Cl) 0.44 min (Method I)Purification with preparative HPLC. E20h

D14 and 3- iodooxetane (M + H)⁺ = 267/269 (Cl) 0.65 min (Method H)Heated over night at 100° C.; Purification with preparative HPLC. E20i

D16 and 3- methyliodide (M + H)⁺ = 293/295 (Cl) 0.64 min (Method J)Purification with preparative HPLC. E20j

D17 and 3- methyliodide (M + H)⁺ = 267/269 (Cl) 0.57 min (Method J)Purification with preparative HPLC.

Intermediate E21

Intermediate D4 (35.0 mg, 0.14 mmol) is mixed with 1 mL dichloromethane.57.7 mg (0.41 mmol) 4-fluorophenylboronic acid, 22.1 μL pyridine and37.4 mg (0.21 mmol) copper(II)acetate are added and the resultingmixture is stirred at room temperature over night. The reaction mixtureis filtered over celite and washed with DCM. The filtrate is extreactedwith sodium bicarbonate, phases are separated and the organic phase isconcentrated. The resulting residue is treated with diisopropyl etherand filtered to yield the product.

MS (ESI⁺): m/z=349/351 (Cl) [M+H]⁺

HPLC (Method G): Rt=0.59 min

The following intermediates were prepared in an analogous manner tointermediate E21:

Mass Structure Starting materials signal(s) R_(f) Value or R_(t) Nr.Comment E22

D1 and cyclopropylboronic acid (M + H)⁺ = 295/297 (Cl) 0.73 min (MethodH) Purification with preparative HPLC. E23

D1 and 3,5- difluorophenylboronic acid (M + H)⁺ = 367/369 (Cl) 0.94 min(Method H) Purification with preparative HPLC. E23b

D1 and 4- fluorophenylboronic acid (M + H)⁺ = 349/351 (Cl) 0.51 min(Method J) Purification with preparative HPLC. E23c

D3 and cyclopropylboronic acid (M + H)⁺ = 281/283 (Cl) 0.35 min (MethodI) Purification with preparative HPLC. E23d

D18-5 and fluorophenylboronic acid (M + H)⁺ = 319/321 (Cl) 0.54 min(Method I) Purification with preparative HPLC.

Intermediate E24-1

To intermediate D3 (150 mg, 0.62 mmol) in 5 mL DMF potassium carbonate(215 mg, 1.56 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(135 μL, 0.94 mmol) are added and the resulting mixture is stirred atroom temperature for 1 h. To the reaction mixture water is added andthen extracted with EA. The combined organic layers are washed with sat.NaCl solution dried and evaporated. The residue is purified bypreparative HPLC (eluent A: water+0.15% TFA, eluent B: ACN) to give theproduct.

MS (ESI⁺): m/z=323/325 (Cl) [M+H]⁺

HPLC (Method I): Rt=0.43 min

The following intermediates were prepared in an analogous manner tointermediate E24-1:

Mass Structure Starting materials signal(s) R_(f) Value or R_(t) Nr.Comment E24- 1b

D3 and 2,2- difluoroethyl- trifluoromethane- sulfonate (M + H)⁺ =306/307 (Cl) 0.39 min (Method J) Purification with preparative HPLC.E24- 1c

D14 and 2,2,2- trifluoroethyl- trifluoromethane- sulfonate (M + H)⁺ =293/295 (Cl) 0.48 min (Method J) Purification with preparative HPLC.E24- 1d

D15 and 2,2,2- trifluoroethyl- trifluoromethane- sulfonate (M + H)⁺ =307/309 (Cl) 0.49 min (Method I) Purification with preparative HPLC.E24- 1e

D14 and 2,2- difluoroethyl- trifluoromethane- sulfonate (M + H)⁺ =275/277 (Cl) 0.43 min (Method J) Purification with preparative HPLC.E24- 1f

D17 and 2,2,2- trifluoroethyl- trifluoromethane- sulfonate (M + H)⁺ =335/337 (Cl) 0.70 min (Method J) Purification with preparative HPLC.

Intermediate E24

Intermediate E24 was prepared in analogy to intermediate E1 startingwith E24-1 and methyliodide.

MS (ESI⁺): m/z=337/339 (Cl) [M+H]⁺

HPLC (Method I): Rt=0.54 min

The following intermediates were prepared in an analogous manner tointermediate E24:

Mass Structure Starting materials signal(s) R_(f) Value or R_(t) Nr.Comment E24b

E23b and methyliodide (M + H)⁺ = 363/365 (Cl) 0.59 min (Method J)Purification with preparative HPLC.

Intermediate E25-1

To intermediate D1 (300 mg, 1.18 mmol) in 5 mL DMF and 5 mL THFpotassium carbonate (326 mg, 2.36 mmol) and1-bromomethyl-2,4-difluoro-benzene (488 mg, 2.36 mmol) are added and theresulting mixture is stirred at 60° C. for 1 h. To the reaction mixturewater and DCM are added and the layers are separated. The organic layeris evaporated in vacuo. The residue is purified by preparative HPLC(eluent A: water+0.15% TFA, eluent B: ACN) to give the product.

MS (ESI⁺): m/z=381/383 (Cl) [M+H]⁺

HPLC (Method L): Rt=1.10 min

The following intermediates were prepared in an analogous manner tointermediate E25-1:

Mass Structure Starting materials signal(s) R_(f) Value or R_(t) Nr.Comment E25- 1b

D3 and 2-(1- bromoethyl) pyridine HBr (M + H)⁺ = 346/348 (Cl) 0.65 min(Method L) Purification with preparative HPLC.

Intermediate E25

Intermediate E25 was prepared in analogy to intermediate E2 startingwith E25-1 and methyliodide.

MS (ESI⁺): m/z=395/397 (Cl) [M+H]⁺

HPLC (Method L): Rt=1.20 min

The following intermediates were prepared in an analogous manner tointermediate E25:

Mass Structure Starting materials signal(s) R_(f) Value or R_(t) Nr.Comment E25b

E25-1b and methyliodide (M + H)⁺ = 360/362 (Cl) 0.78 min (Method L)Purification with preparative HPLC. E25c

E23c and methyliodide (M + H)⁺ = 295/297 (Cl) 0.45 min (Method I)Purification with preparative HPLC. E25d

E24-1b and methyliodide (M + H)⁺ = 320/321 (Cl) 0.49 min (Method J)Purification with preparative HPLC. E25e

E24-1c and methyliodide (M + H)⁺ = 307/309 (Cl) 0.59 min (Method J)Purification with preparative HPLC. E25f

E24-1d and methyliodide (M + H)⁺ = 321/323 (Cl) 0.59 min (Method I)Purification with preparative HPLC. E25g

E20h and methyliodide (M + H)⁺ = 281/283 (Cl) 0.85 min (Method H)Purification with preparative HPLC. E25h

E24-1e and methyliodide (M + H)⁺ = 289/291 (Cl) 0.53 min (Method J)Purification with preparative HPLC.

Intermediate E28

To intermediate E20e (115 mg, 0.337 mmol) in THF (15 mL) under argonatmosphere methylmagnesiumbromide (1.4 mol/L in THF/toluene, 1.446 mL,2.025 mmol) is added under cooling and afterwards the reaction mixtureis warmed to room temperature. 30 mL ammonia chloride solution (27%) isadded under cooling and the mixture is extracted with EA. The combinedorganic layers are concentrated in vacuo and the residue is purified bypreparative HPLC (eluent A: water+0.15° A) TFA, eluent B: ACN) to givethe product.

MS (ESI⁺): m/z=327/329 (Cl) [M+H]⁺

HPLC (Method N): Rt=0.95 min.

Intermediate E29-1

Intermediate D3 (300.0 mg, 1.247 mmol) is mixed with 16 mL DCM. Lithiumtrihydroxy(5-(trifluoromethyl)pyridin-2-yl)borate (401.8 mg, 1.870mmol), pyridine (197 μL, 2.493 mmol), triethylamine (175 μL, 1.247 mmol)and copper(II)acetate (452.9 mg, 2.493 mmol) are added and the resultingmixture is stirred at 60° C. over night. The reaction mixture isfiltered over celite and washed with DCM. The filtrate is extracted withsodium bicarbonate, phases are separated and the organic phase isconcentrated. The residue is purified by preparative HPLC (eluent A:water+0.15% TFA, eluent B: ACN) to give the product.

MS (ESI⁺): m/z=386/388 (Cl) [M+H]⁺

HPLC (Method N): Rt=0.97 min

Intermediate E29

Intermediate E29 was prepared in analogy to intermediate E2 startingwith E29-1 and methyliodide.

MS (ESI⁺): m/z=400/402 (Cl) [M+H]⁺

Intermediate F1

Intermediate F1 was prepared according to WO 2010/089292.

Intermediate F2

Intermediate F2 was prepared according to WO 2011/014535.

Intermediate F3

Intermediate F3 was prepared according to WO 2010/089292.

Intermediate F4

Intermediate F4 was prepared according to WO 2009/075874.

Intermediate F5

Intermediate F5 was prepared according to WO 2011/014535.

Intermediate F6

Intermediate F6 was prepared according to WO 2009/103652.

Intermediate F7

Intermediate F7 was prepared according to WO 2010/132015.

Intermediate F8-1

To 2-methylimidazole (500.0 mg, 6.090 mmol) in DMF (10 mL) potassiumcarbonate (1.683 g, 12.180 mmol) and 4-fluoro-3-methoxynitrobenze (1.042g, 6.090 mmol) are added and the resulting mixture is stirred at 85° C.for 12 h in a pressure tube. Afterwards the solvent is removed in vacuo,sodium bicarbonate solution (9%) is added and extracted with EA. Thecombined organic layers are washed with sat. sodium chloride solution,dried, filtered and evaporated to get the product.

MS (ESI⁺): m/z=234 [M+H]⁺

Intermediate F8

Intermediate F8-1 is hydrogenated (hydrogen atmosphere, 50 psi) inmethanol (30 mL) with raney nickel at room temperature for 20 h. Thereaction mixture is filtered and the filtrate is concentrated in vacuoto get the product.

MS (ESI⁺): m/z=204 [M+H]⁺

HPLC (Method H): Rt=0.64 min

Example 1

Intermediate E1 (100 mg, 0.354 mmol) and intermediate F1 (144 mg, 0.707mmol) are dissolved in dioxane (3 mL). The mixture is degassed withnitrogen for 5 min.Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)[2-(2-aminoethyl)-phenyl]-palladium(II)(13.1 mg, 0.018 mmol) and cesium carbonate (230 mg, 0.707 mmol) areadded subsequently. The reaction mixture is heated to 140° C. for 2 husing a microwave oven. DCM is added and the reaction mixture isfiltered over celite and washed with DCM. The filtrate is concentratedin vacuo and the residue is purified by preparative HPLC (eluent A:water+0.1% conc. ammonia, eluent B: MeOH) to give the product as asolid.

MS (ESI⁺): m/z=451 [M+H]⁺

HPLC (Method A): Rt=1.07 min

In analogy to the preparation of example 1 the following compounds areobtained:

Mass Nr. Structure Educt 1 Educt 2 signal(s) R_(t)  2

E1 F2 (M + H)⁺ = 450 0.82 min. (Method A)  3

E1 F3 (M + H)⁺ = 422 0.94 min (Method A)  4

E2 F2 (M + H)⁺ = 464 0.86 min (Method A)  5

E2 F3 (M + H)⁺ = 436 0.94 min (Method A)  6

E3 F2 (M + H)⁺ = 436 1.35 min (Method B)  7

E3 F1 (M + H)⁺ = 437 1.37 min (Method B)  8

E3 F3 (M + H)⁺ = 408 1.25 min (Method B)  9

D2 F2 (M + H)⁺ = 436 1.30 min (Method B) 10

D4 F2 (M + H)⁺ = 422 1.28 min (Method B) 11

E4 F2 (M + H)⁺ = 494 1.38 min (Method B) 12

E4 F4 (M + H)⁺ = 475 1.41 min (Method B) 13

E4 F5 (M + H)⁺ = 495 1.29 min (Method B) 14

E5 F4 (M + H)⁺ = 461 1.40 min (Method B) 15

E5 F5 (M + H)⁺ = 481 1.27 min (Method B) 16

E5 F2 (M + H)⁺ = 480 1.35 min (Method B) 17

E6 F2 (M + H)⁺ = 478 1.46 min (Method B) 18

E3 F6 (M + H)⁺ = 431 1.29 min (Method B) 19

E7 F6 (M + H)⁺ = 417 1.21 min (Method B) 20

E7 F2 (M + H)⁺ = 422 1.26 min (Method B) 21

E8 F2 (M + H)⁺ = 478 1.24 min (Method B) 22

E9 F2 (M + H)⁺ = 506 1.23 min (Method B) 23

E11 F2 (M + H)⁺ = 464 1.35 min (Method B) 24

E10 F2 (M + H)⁺ = 604 1.30 min (Method B) 25

D8 F2 (M + H)⁺ = 452 1.19 min (Method B) 26

E12 F2 (M + H)⁺ = 520 1.24 min (Method B) 27

E13 F2 (M + H)⁺ = 466 1.20 min (Method F) 28

E14 F2 (M + H)⁺ = 464 1.16 min (Method B) 29

E15 F2 (M + H)⁺ = 478 1.39 min (Method B) 30

E17 F2 (M + H)⁺ = 536 1.44 min (Method B) 31

E17 F1 (M + H)⁺ = 537 1.47 min (Method B) 32

E18 F2 (M + H)⁺ = 492 1.43 min (Method B) 33

D7 F2 (M + H)⁺ = 464 1.40 min (Method B) 34

E19 F2 (M + H)⁺ = 464 1.35 min (Method B) 35

E19 F6 (M + H)⁺ = 459 1.30 min (Method B) 36

E20 F2 (M + H)⁺ = 496 1.12 min (Method A) 37

E20 F3 (M + H)⁺ = 468 1.25 min (Method A) 37a

E21 F2 (M + H)⁺ = 516 1.28 min (Method F) 37b

E20a F2 (M + H)⁺ = 476 0.98 min (Method H) 37c

E20b F2 (M + H)⁺ = 548 0.43 min (Method I) 37d

E1b F2 (M + H)⁺ = 518 0.50 min (Method J) 37e

E24 F2 (M + H)⁺ = 504 0.39 min (Method I) 37f

E24b F2 (M + H)⁺ = 530 0.42 min (Method I) 37g

E25c F2 (M + H)⁺ = 462 0.79 min (Method O) 37h

E25d F2 (M + H)⁺ = 486 0.99 min (Method H) 37i

E1c F7 (M + H)⁺ = 435 0.78 min (Method L) 37j

E25 F2 (M + H)⁺ = 562 0.49 min (Method P) 37k

E25b F2 (M + H)⁺ = 527 1.02 min (Method H)

Example 38

2′-Chloro-8′-cyclopentyl-5′-methyl-5′H-spiro[cyclopropane-1,7′-pteridin]-6′(8′H)-one(100 mg, 0.342 mmol, prepared according to WO 2004-076454) andintermediate F2 (76.4 mg, 0.376 mmol) are mixed with 4-methyl-2-pentanol(1 mL) and stirred for 10 min. at 55° C. p-Toluenesulfonic acid (12% inacetic acid, 1.15 mL, 0.854 mmol) is added and the reaction mixture isstirred for 48 h at 70° C. The mixture is concentrated in vacuo and theresidue is purified by preparative HPLC (eluent A: water+0.1% conc.ammonia, eluent B: MeOH) to give the product as a solid.

MS (ESI⁺): m/z=460 [M+H]⁺

HPLC (Method C): Rt=0.60 min

Example 39

Intermediate E20c (40.0 mg, 0.135 mmol) and intermediate F2 (35.6 mg,0.175 mmol) are dissolved in dioxane (4.5 mL). The mixture is degassedwith nitrogen for 5 min.Dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (6.42 mg,0.013 mmol), palladium(II)acetate (3.03 mg, 0.013 mmol) and cesiumcarbonate (184 mg, 0.566 mmol) are added subsequently. The reactionmixture is heated to 140° C. for 45 min using a microwave oven. DCM isadded and the reaction mixture is filtered over celite and washed withDCM. The filtrate is concentrated in vacuo and the residue is purifiedby preparative HPLC (eluent A: water+0.1% conc. ammonia, eluent B: MeOH)to give the product as a solid.

MS (ESI⁺): m/z=464 [M+H]⁺

HPLC (Method H): Rt=1.10 min

In analogy to the preparation of example 39 the following compounds areobtained:

Mass Nr. Structure Educt 1 Educt 2 signal(s) R_(t) 40

E28 F1 (M + H)⁺ = 495 1.09 min. (Method H)

Example 41

Intermediate E20f (24.0 mg, 0.094 mmol) and intermediate F2 (24.9 mg,0.123 mmol) are dissolved in dioxane (4.5 mL). The mixture is degassedwith nitrogen for 5 min. XPhos (4.49 mg, 0.009 mmol),palladium(II)acetate (2.12 mg, 0.009 mmol) and cesium carbonate (35.5mg, 0.283 mmol) are added subsequently. The reaction mixture is heatedto 140° C. for 45 min using a microwave oven. The reaction mixture isfiltered over celite, washed with DCM and concentrated in vacuo. Theresidue is purified by preparative HPLC (eluent A: water+0.1% conc.ammonia, eluent B: MeOH) to give the product as a solid.

MS (ESI⁺): m/z=422 [M+H]⁺

HPLC (Method H): Rt=0.89 min

In analogy to the preparation of example 42 the following compounds areobtained:

Mass Nr. Structure Educt 1 Educt 2 signal(s) R_(t) 42

E20g F2 (M + H)⁺ = 464 0.96 min. (Method H) 43

E1e F2 (M + H)⁺ = 420 1.03 min. (Method H) 44

E25e F2 (M + H)⁺ = 474 1.09 min. (Method H) 45

E25f F1 (M + H)⁺ = 489 1.22 min. (Method H) 46

E23d F2 (M + H)⁺ = 486 1.10 min. (Method H) 47

E25g F2 (M + H)⁺ = 448 0.92 min. (Method H) 48

E29 F2 (M + H)⁺ = 567 1.09 min. (Method H) 49

E20i F7 (M + H)⁺ = 461 1.09 min. (Method H) 50

E25e F7 (M + H)⁺ = 475 1.06 min. (Method H) 51

E25e F8 (M + H)⁺ = 474 1.06 min. (Method H) 52

E25h F2 (M + H)⁺ = 456 1.03 min. (Method H) 53

E20j F2 (M + H)⁺ = 434 1.08 min. (Method H) 54

E24-1f F2 (M + H)⁺ = 502 1.21 min. (Method H) 55

E1f F2 (M + H)⁺ = 488 0.45 min. (Method J)

1. A compound of the formula I

wherein A is selected from the group A^(a) consisting of a heteroarylgroup with 5 or 6 ring atoms containing one to three heteroatomsindependently selected from N, O, S, wherein above mentioned heteroarylgroups may optionally be substituted with 1 or 2 substituentsindependently selected from the group consisting of halogen, cyano,C₁₋₆-alkyl-, HO—C₁₋₆-alkyl-, which is optionally fluorinated with 1 to13 fluorine atoms, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₃-alkyl-,C₁₋₄-alkyl-O— which is optionally fluorinated with 1 to 9 fluorine atomsand (C₁₋₄-alkyl)₃Si—; B is selected from the group B^(a) consisting of

wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-, pyridazinyland pyrazinyl groups may optionally be substituted with 1 or 2substituents independently selected from the group consisting of HO—,halogen, cyano, C₁₋₆-alkyl- which is optionally fluorinated with 1 to 13fluorine atoms, C₃₋₆-cycloalkyl-O— and C₁₋₆-alkyl-O— which is optionallyfluorinated with 1 to 13 fluorine atoms; D is selected from the groupD^(a) consisting of a 4- to 12-membered mono-, bicyclic or bridgedheterocyclyl group, or a 3- to 12-membered mono- or bicyclic carbocyclylgroup, wherein above mentioned group D^(a) may optionally be substitutedwith 1 to 4 substituents independently selected from the groupconsisting of halogen, cyano, C₁₋₆-alkyl- which is optionallyfluorinated with 1 to 13 fluorine atoms, C₃₋₆-cycloalkyl-, heterocyclyl,aryl, aryl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl-, HC(O)—,C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—, C₁₋₄-alkyl-O—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, HO—, oxo, C₁₋₆-alkyl-O— which is optionallyfluorinated with 1 to 13 fluorine atoms, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, aryl-O—, heteroaryl-O—, H₂N—, (C₁₋₄-alkyl)₂N—,azetidinyl, pyrrolidinyl and (C₁₋₄-alkyl)(C₁₋₃-alkyl-C(O))N—, whereinabove mentioned aryl-C(O)—, aryl-O—, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,heteroaryl-C₁₋₃-alkyl- and heteroaryl-O— groups may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₃C—, F₂HCO—, FH₂CO—,heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, H₂N—,(C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which isoptionally fluorinated with 1 to 13 fluorine atoms; W is selected fromthe group W^(a) consisting of —(R⁷)N— and —O—; R¹ is selected from thegroup R^(1a) consisting of H, C₁₋₈-alkyl-, C₂₋₈-alkenyl-, C₂₋₈-alkynyl-,carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—C₁₋₃-alkyl-, R⁴O—, R⁴S(O)_(m)— with m=0,1, 2, wherein above mentioned C₁₋₈-alkyl-, C₂₋₈-alkenyl-, C₂₋₈-alkynyl-,carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,heteroaryl-C₁₋₃-alkyl- and R⁴R⁵N—C₁₋₃-alkyl- groups may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of HO—, oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, H₂N—,(C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,(C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl-and C₁₋₆-alkyl-, and wherein above mentioned C₁₋₄-alkyl-O—,C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groupsmay optionally be substituted with 1 to 13 fluorine atoms; R² isselected from the group R^(2a) consisting of H, C₁₋₈-alkyl-,C₂₋₈-alkenyl-, C₂₋₈-alkynyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,C-linked heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-,heteroaryl, heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—, R⁴R⁵N—C₁₋₃-alkyl-,R⁴R⁵N—C(O)— and R⁴O—, wherein above mentioned C₁₋₈-alkyl-,C₂₋₈-alkenyl-, C₂₋₈-alkynyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,C-linked heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-,heteroaryl and heteroaryl-C₁₋₃-alkyl-groups may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of HO—, oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, H₂N—,(C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—,(C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl-,C₃₋₅-cycloalkyl- and C₁₋₆-alkyl-, and wherein above mentionedC₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl- andC₁₋₆-alkyl- may optionally be substituted with 1 to 13 fluorine atoms;R³ is selected from the group R^(3a) consisting of H, C₁₋₈-alkyl-,C₂₋₈-alkenyl-, C₂₋₈-alkynyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,C-linked heterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-,heteroaryl, heteroaryl-C₁₋₃-alkyl-, R⁴R⁵N—, R⁴R⁵N—C₁₋₃-alkyl-, and R⁴O—,wherein above mentioned C₁₋₈-alkyl-, C₂₋₈-alkenyl-, C₂₋₈-alkynyl-,carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl andheteroaryl-C₁₋₃-alkyl-groups may optionally be substituted with 1 to 3substituents independently selected from the group consisting of HO—,oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen,F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, andwherein above mentioned C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, (C₁₋₄-alkyl)₂N—, (C₁₋₄-alkyl)-C(O)—,(C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groups may optionally besubstituted with 1 to 13 fluorine atoms; R⁴, R⁵ are selectedindependently of each other from the group R^(4a)/R^(5a) consisting ofH, C₁₋₆-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,carbocyclyl-O—C₂₋₄-alkyl-, heterocyclyl, heterocyclyl-C₁₋₆-alkyl-,heterocyclyl-O—C₂₋₄-alkyl-, aryl, aryl-C₁₋₃-alkyl-, aryl-O—C₂₋₃-alkyl-,heteroaryl, heteroaryl-C₁₋₃-alkyl- and heteroaryl-O—C₂₋₃-alkyl-, whereinabove mentioned C₁₋₆-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-,carbocyclyl-O—C₂₋₄-alkyl-, heterocyclyl, heterocyclyl-C₁₋₆-alkyl- orheterocyclyl-O—C₂₋₄-alkyl- groups may optionally be substituted with 1to 3 substituents independently selected from the group consisting ofhalogen, cyano, HO—, oxo, C₁₋₄-alkyl-O— which is optionally fluorinatedwith 1 to 9 fluorine atoms, C₁₋₄-alkyl-O—C(O)—, HO—C₁₋₄-alkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl, (C₁₋₄-alkyl)₂N—,(C₁₋₃-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is optionally fluorinatedwith 1 to 13 fluorine atoms, wherein above mentioned aryl-,aryl-C₁₋₃-alkyl-, aryl-O—C₂₋₃-alkyl-, heteroaryl-,heteroaryl-C₁₋₃-alkyl- and heteroaryl-O—C₂₋₃-alkyl- groups mayoptionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—,FH₂CO—, heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro,(R⁶)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which is optionally fluorinatedwith 1 to 13 fluorine atoms, or R^(4a) and R^(5a) form together with thenitrogen atom to which they are attached a 4-12-membered mono-, bicyclicor bridged ring system optionally containing one or two double bondsand/or one aromatic ring and optionally containing one or two additionalheteroatoms selected from the group consisting of —O—, —S—, —S(O)—,—S(O)₂—, —N(R⁶)—, wherein 2 geminal hydrogen atoms of the 4-12-memberedmono- or bicyclic ring system may be replaced by a —(CH₂)₁₋₅— group andwherein one —(CH₂)— group of the —(CH₂)₁₋₅— group may be replaced by —O—or —N(R⁶)— and wherein above mentioned 4-12-membered mono-, bicyclic orbridged ring system may optionally be substituted with 1 or 2substituents independently selected from the group consisting ofhalogen, cyano, aryl, heteroaryl, aryl-C₁₋₃-alkyl-, C₁₋₆-alkyl- which isoptionally fluorinated with 1 to 13 fluorine atoms, heterocyclyl, HO—,oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-O—C(O)—,HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₆-cycloalkyl-O—C₁₋₄-alkyl-,heterocyclyl-O—, heterocyclyl-O—C₁₋₄-alkyl-, aryl-O—, heteroaryl-O— and(R⁶)₂N—, wherein the directly above mentioned aryl, aryl-C₁₋₃-alkyl-,aryl-O—, heteroaryl-O—, and heteroaryl groups may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, amino,(C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which isoptionally fluorinated with 1 to 13 fluorine atoms; R⁶ is selectedindependently of each other from the group R^(6a) consisting of H,C₁₋₆-alkyl-, C₃₋₆-cycloalkyl, heterocyclyl, heteroaryl, HC(O)—,C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—, C₁₋₄-alkyl-O—C(O)—and (C₁₋₄-alkyl)₂N—C(O)—, wherein above mentioned C₁₋₆-alkyl-,C₃₋₆-cycloalkyl-, C₁₋₆-alkyl-C(O)— and C₃₋₆-cycloalkyl-C(O)— groups mayoptionally be substituted with 1-13 fluorine atoms, wherein the abovementioned aryl-C(O)— and heteroaryl group may optionally be substitutedwith 1 to 3 substituents independently selected from the groupconsisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—,heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—, nitro, amino,(C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which isoptionally fluorinated with 1 to 13 fluorine atoms; R⁷ is selected fromthe group R^(7a) consisting of H and C₁₋₅-alkyl- which is optionallyfluorinated with 1 to 13 fluorine atoms, or a salt thereof.
 2. Acompound according to claim 1, wherein A is selected from the groupA^(b) consisting of

wherein above mentioned groups may optionally be substituted with 1 or 2substituents independently selected from the group consisting ofhalogen, cyano, and C₁₋₆-alkyl- which is optionally fluorinated with 1to 13 fluorine atoms.
 3. A compound according to claim 1, wherein A isselected from the group A^(e) consisting of

wherein above mentioned groups may optionally be substituted with 1 or 2substituents independently selected from the group consisting of halogenand C₁₋₃-alkyl- which is optionally fluorinated with 1 to 7 fluorineatoms.
 4. A compound according to claim 1, wherein B is selected fromthe group B^(b) consisting of

wherein above mentioned phenyl- and pyridinyl-groups may optionally besubstituted with 1 or 2 substituents independently selected from thegroup consisting of HO—, halogen, cyano, C₁₋₆-alkyl- which is optionallyfluorinated with 1 to 13 fluorine atoms, C₃₋₆-cycloalkyl-O— andC₁₋₆-alkyl-O— which is optionally fluorinated with 1 to 13 fluorineatoms.
 5. A compound according to claim 1, wherein D is selected fromthe group D^(b) consisting of

wherein above mentioned ring system D^(b) may optionally be substitutedwith 1 to 4 substituents independently selected from the groupconsisting of halogen, cyano, C₁₋₆-alkyl- which is optionallyfluorinated with 1 to 13 fluorine atoms, C₃₋₆-cycloalkyl-, heterocyclyl,aryl, aryl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl-, HC(O)—,C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, aryl-C(O)—, C₁₋₄-alkyl-O—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, HO—, oxo, C₁₋₆-alkyl-O— which is optionallyfluorinated with 1 to 13 fluorine atoms, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, aryl-O—, heteroaryl-O—, H₂N—, (C₁₋₄-alkyl)₂N—,azetidinyl, pyrrolidinyl and (C₁₋₄-alkyl)(C₁₋₃-alkyl-C(O))N—, andwherein above mentioned aryl-C(O)—, aryl-O—, aryl, aryl-C₁₋₃-alkyl-,heteroaryl, heteroaryl-C₁₋₃-alkyl- and heteroaryl-O— groups mayoptionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of HO—, C₁₋₄-alkyl-O—, F₃CO—, F₃C—,F₂HCO—, FH₂CO—, heterocyclyl-O—, cyano, halogen, F₅S—, (C₁₋₄-alkyl)₃Si—,nitro, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- which isoptionally fluorinated with 1 to 13 fluorine atoms.
 6. A compoundaccording to claim 1, wherein D is selected from the group D^(e)consisting of

wherein above mentioned rings D^(e) may optionally be substituted with 1to 4 substituents independently selected from the group consisting ofhalogen, cyano, C₁₋₆-alkyl- which is optionally fluorinated with 1 to 13fluorine atoms, C₃₋₆-cycloalkyl-, phenyl- wherein above mentioned phenylmay optionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—,FH₂CO—, cyano, halogen, F₅S— and C₁₋₆-alkyl- which is optionallyfluorinated with 1 to 13 fluorine atoms.
 7. A compound according toclaim 1, wherein W is selected from the group W^(b) consisting of—(R⁷)N—.
 8. A compound according to claim 1, wherein R¹ is selected fromthe group R^(1b) consisting of H, C₁₋₈-alkyl-, carbocyclyl,carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, heteroaryl, heteroaryl-C₁₋₃-alkyl-,R⁴R⁵N—C₁₋₃-alkyl-, R⁴O—, and R⁴S(O)_(m)— with m=0, 1, 2 wherein abovementioned C₁₋₈-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linkedheterocyclyl, heterocyclyl-C₁₋₃-alkyl-, heteroaryl,heteroaryl-C₁₋₃-alkyl- and R⁴R⁵N—C₁₋₃-alkyl- groups may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of HO—, oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, cyano, halogen, H₂N—, (C₁₋₄-alkyl)₂N—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, andwherein above mentioned C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, (C₁₋₄-alkyl)₂N—, (C₁₋₄-alkyl)-C(O)—,(C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- may optionally be substitutedwith 1 to 13 fluorine atoms.
 9. A compound according to claim 1, whereinR² is selected from the group R^(2b) consisting of H, C₁₋₈-alkyl-,carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-, heteroaryl,heteroaryl-C₁₋₃-alkyl- and R⁴R⁵N—C₂₋₃-alkyl-, wherein above mentionedC₁₋₈-alkyl-, carbocyclyl, carbocyclyl-C₁₋₃-alkyl-, C-linkedheterocyclyl, heterocyclyl-C₁₋₃-alkyl-, aryl, aryl-C₁₋₃-alkyl-,heteroaryl and heteroaryl-C₁₋₃-alkyl- groups may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of HO—, oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, cyano, halogen, H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₅-cycloalkyl- andC₁₋₆-alkyl-, and wherein above mentioned C₁₋₄-alkyl-O—,C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, C₃₋₆-cycloalkyl- andC₁₋₆-alkyl- groups may optionally be substituted with 1 to 13 fluorineatoms.
 10. A compound according to claim 1, wherein R³ is selected fromthe group R^(3b) consisting of H, C₁₋₈-alkyl-, carbocyclyl,carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, aryl-C₁₋₃-alkyl-, heteroaryl-C₁₋₃-alkyl- andR⁴R⁵N—C₂₋₃-alkyl-, wherein above mentioned C₁₋₈-alkyl-, carbocyclyl,carbocyclyl-C₁₋₃-alkyl-, C-linked heterocyclyl,heterocyclyl-C₁₋₃-alkyl-, aryl-C₁₋₃-alkyl-, andheteroaryl-C₁₋₃-alkyl-groups may optionally be substituted with 1 to 3substituents independently selected from the group consisting of HO—,oxo, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, cyano, halogen,H₂N—, (C₁₋₄-alkyl)₂N—, (H₂N)—C(O)—, (C₁₋₄-alkyl)-C(O)—,(C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—, (C₁₋₄-alkyl)₂N—C(O)—,C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl-, and wherein above mentionedC₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, (C₁₋₄-alkyl)₂N—,(C₁₋₄-alkyl)-C(O)—, (C₁₋₄-alkyl)-O—C(O)—, (C₁₋₄-alkyl)-HN—C(O)—,(C₁₋₄-alkyl)₂N—C(O)—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₆-alkyl- groupsmay optionally be substituted with 1 to 13 fluorine atoms;
 11. Acompound according to claim 1, wherein R⁴, R⁵ are selected independentlyof each other from the group R^(4b)/R^(5b) consisting of H, C₁₋₆-alkyl-,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, heterocyclyl, heterocyclyl-C₁₋₆-alkyl-,aryl, aryl-C₁₋₃-alkyl-, aryl-O—C₂₋₃-alkyl-, heteroaryl andheteroaryl-C₁₋₃-alkyl-, wherein above mentioned C₁₋₆-alkyl-,C₃₋₇-cycloalkyl-, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, heterocyclyl or heterocyclyl-C₁₋₆-alkyl-groups may optionally be substituted with 1 to 3 substituentsindependently selected from the group consisting of fluoro, HO—, oxo,C₁₋₄-alkyl-O— which is optionally fluorinated with 1 to 9 fluorineatoms, HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl,(C₁₋₃-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is optionally fluorinatedwith 1 to 13 fluorine atoms, wherein above mentioned aryl-,aryl-C₁₋₃-alkyl-, aryl-O—C₂₋₃-alkyl-, heteroaryl- andheteroaryl-C₁₋₃-alkyl- groups may optionally be substituted with 1 to 3substituents independently selected from the group consisting ofC₁₋₄-alkyl-O—, F₃CO—, F₂HCO—, FH₂CO—, cyano, halogen,(C₁₋₄-alkyl)₂N—C(O)—, and C₁₋₆-alkyl- which is optionally fluorinatedwith 1 to 13 fluorine atoms, or R^(4b) and R^(5b) form together with thenitrogen atom to which they are attached a 4-12-membered mono-, bicyclicor bridged ring system optionally containing one double bond and/or onearomatic ring and optionally containing one additional heteroatomselected from the group consisting of —O—, —N(R⁶)—, wherein 2 geminalhydrogen atoms of the 4-12-membered mono- or bicyclic ring may bereplaced by a —(CH₂)₁₋₅— group and wherein one —(CH₂)— group of the—(CH₂)₁₋₅— group may be replaced by —O— or —N(R⁶)— and wherein abovementioned 4-12-membered mono-, bicyclic or bridged ring system mayoptionally be substituted with 1 or 2 substituents independentlyselected from the group consisting of fluoro, aryl, heteroaryl,C₁₋₆-alkyl- which is optionally fluorinated with 1 to 13 fluorine atoms,heterocyclyl, HO—, oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—,HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, heterocyclyl-O— and (R⁶)₂N—,wherein the directly above mentioned aryl and heteroaryl groups mayoptionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of C₁₋₄-alkyl-O—, F₃CO—, F₂HCO—,FH₂CO—, cyano, halogen, (C₁₋₄-alkyl)₂N—C(O)— and C₁₋₆-alkyl- which isoptionally fluorinated with 1 to 13 fluorine atoms.
 12. A compoundaccording to claim 1, wherein R⁴, R⁵ are selected independently of eachother from the group R^(4e)/R^(5e) consisting of H, C₁₋₆-alkyl-,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl-,C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, azetidinyl, pyrrolidinyl, piperidinyl,azepanyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl,dioxepanyl, tetrahydrothiophenyl, 1-oxo-tetrahydrothiophenyl1,1-dioxo-tetrahydrothiophenyl, azetidinyl-C₁₋₃-alkyl-,pyrrolidinyl-C₁₋₃-alkyl-, piperidinyl-C₁₋₃-alkyl-,piperazinyl-C₁₋₃-alkyl-, oxetanyl-C₁₋₃-alkyl-,tetrahydrofuryl-C₁₋₃-alkyl-, tetrahydropyranyl-C₁₋₃-alkyl-, whereinabove mentioned C₁₋₆-alkyl-, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl-, C₃₋₇-cycloalkyl-O—C₂₋₄-alkyl-, azetidinyl,pyrrolidinyl, piperidinyl, azepanyl, oxetanyl, tetrahydrofuryl,tetrahydropyranyl, oxepanyl, dioxepanyl, tetrahydrothiophenyl,1-oxo-tetrahydrothiophenyl 1,1-dioxo-tetrahydrothiophenyl,azetidinyl-C₁₋₃-alkyl-, pyrrolidinyl-C₁₋₃-alkyl-,piperidinyl-C₁₋₃-alkyl-, piperazinyl-C₁₋₃-alkyl-, oxetanyl-C₁₋₃-alkyl-,tetrahydrofuryl-C₁₋₃-alkyl-, tetrahydropyranyl-C₁₋₃-alkyl-groups mayoptionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of fluoro, HO—, oxo, C₁₋₄-alkyl-O—,HO—C₁₋₄-alkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl- and C₁₋₃-alkyl- which isoptionally fluorinated with 1 to 7 fluorine atoms, or R^(4e) and R^(5e)form together with the nitrogen atom to which they are attached a ringsystem selected from the group consisting of

wherein above mentioned monocyclic rings may optionally be substitutedwith 1 or 2 substituents independently selected from the groupconsisting of fluoro, C₁₋₃-alkyl- which is optionally fluorinated with 1to 7 fluorine atoms, HO—, oxo, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—,HO—C₁₋₄-alkyl- and C₁₋₄-alkyl-O—C₁₋₄-alkyl-.
 13. A compound according toclaim 1, wherein R⁶ is selected independently of each other from thegroup R^(6b) consisting of H, C₁₋₆-alkyl-, C₃₋₆-cycloalkyl, oxetanyl,tetrahydrofuryl, tetrahydropyranyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, thiazolyl, oxadiazolyl, oxazolyl, HC(O)—,C₁₋₆-alkyl-C(O)—, C₃₋₆-cycloalkyl-C(O)—, phenyl-C(O)—,C₁₋₄-alkyl-O—C(O)— and (C₁₋₄-alkyl)₂N—C(O)—, wherein above mentionedC₁₋₆-alkyl-, C₃₋₆-cycloalkyl-, C₁₋₆-alkyl-C(O)— andC₃₋₆-cycloalkyl-C(O)— groups may optionally be substituted with 1-13fluorine atoms, wherein the aforementioned phenyl-C(O)—, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl oxadiazolyland oxazolyl groups may optionally be substituted with 1 to 3substituents independently selected from the group consisting ofC₁₋₄-alkyl-O—, F₃C—, F₃CO—, F₂HCO—, FH₂CO—, cyano, halogen, andC₁₋₃-alkyl-.
 14. A compound according to claim 1, wherein R⁷ is selectedfrom the group R^(7b) consisting of H.
 15. A pharmaceutically acceptablesalt of a compound according to any one of claims 1-14.
 16. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 17. A method for treatingAlzheimer's disease which comprises administering to a human sufferingfrom the same a therapeutically effective amount of a compound accordingto claim 1.